Arrdc1-mediated microvesicle-based inflammation modulation

Abstract

Provided herein are compositions and methods for ARRDC1-mediated microvesicle-based modulation of inflammatory gene targets, as well as inflammation and inflammatory disorders.

Description

[0001] Attorney Docket No.54926-0014WO1 ARRDC1-MEDIATED MICROVESICLE-BASED INFLAMMATION MODULATION CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 466,915, filed on May 16, 2023, and U.S. Provisional Patent Application No. 63 / 533,811, filed on August 21, 2023, the contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD Provided herein are compositions and methods for ARRDC1-mediated microvesicle-based modulation of inflammatory gene targets, as well as inflammation and inflammatory disorders. BACKGROUND A need exists for improved modulators of inflammation (e.g., autoinflammatory disorders). The present invention addresses this and other deficiencies in the art. SUMMARY In vivo gene editing therapies offer the transformative potential to cure, ameliorate, or prevent an array of diseases. However, broader therapeutic applications, beyond targeting hepatocytes or ex vivo gene editing, have been limited by the inability to efficiently and safely deliver gene editing technologies to disease- affected tissues and cell types. Described herein are engineered the human ARMMs (ARrestin-domain 1 Mediated Microvesicles) as a safe, targeted, and re-dosable therapeutic platform for the delivery of therapeutic cargo (e.g., CRISPR / Cas9 gene editing complexes) in vivo. The protein ARRDC1, which is the principal driver of ARMM formation, is used as a recruitment handle to actively load engineered vesicles. That therapeutic payload-loaded ARMMs are engineered versions of naturally existing vesicles enables this delivery system to overcome various limitations of existing delivery technologies, such as toxicity, low specificity, instability, and immunogenicity. Attorney Docket No.54926-0014WO1 As described herein, a scalable cell-based production system readily loads the therapeutic payloads (e.g., CRISPR / Cas9 protein complexed to guide RNA (gRNA)) into ARMMs and achieves high loading efficiencies, unparalleled by other platforms. Functional delivery of Cas9 / gRNA complexes by ARMMs was first demonstrated in vitro with multiple gRNA sequences targeting several genomic loci in a range of human and murine cell types, including primary and post-mitotic cells. In vivo administration of ARMMs yielded 60-70% editing after a single dose. These results highlight the therapeutic potential of ARMMs-based delivery of CRISPR / Cas9 in disease modification. This invention relates to the discovery that molecules, such as proteins and nucleic acids, including ribonucleic acids (RNAs), as well as small molecules, can be loaded into microvesicles, specifically ARRDC1-mediated microvesicles (ARMMs), and used to modulate inflammation. In addition, the ARMM delivery systems, described herein, address limitations of current delivery systems that prevent the safe and efficient delivery of proteins and nucleic acids (e.g., RNAs (including both RNA coding for proteins and non-coding RNA) to the retina. As ARMMs are derived from an endogenous budding pathway, they are unlikely to elicit a strong immune response, unlike viral delivery systems, which are known to trigger inflammatory responses. (See, Sen et al., “Cellular unfolded protein response against viruses used in gene therapy,” Front Microbiology, 5:250, 1-16 (2014)). Additionally, ARMMs allow for the specific packaging of many types and classes of potentially therapeutic molecules (e.g., biological molecules, such as a protein or nucleic acid (e.g., DNA plasmid, mRNA, miRNA, or shRNA), or small molecules). While the present invention is not intended to be limited to any particular mechanism(s), it is contemplated, in certain embodiments, ARMMs can be delivered by fusion with or uptake by, specific recipient cells and tissues by incorporating antibodies or other types of targeting or tropism determinant molecules into or onto the ARMMs so as to recognize tissue-specific markers. ARMMs are microvesicles that are distinct from exosomes which, like budding viruses, are produced by direct plasma membrane budding (“DPMB”). DPMB is driven by a specific interaction of TSG101 with a tetrapeptide PSAP (SEQ ID NO: 35) motif of the arrestin-domain-containing protein ARRDC1 accessory protein, which is localized to the plasma membrane through its arrestin domain. ARMMs have been described in detail, for example, in PCT application number Attorney Docket No.54926-0014WO1 PCT / US2013 / 024839, filed February 6, 2013 (published as WO 2013 / 119602 A1 on August 15, 2013) by Lu, Q., et al., and entitled “Arrdc1-Mediated Microvesicles (ARMMs) and Uses Thereof,” as well as in U.S. Pat. Nos.: 9,737,480; 9,816,080; 10,260,055; and PCT Publication WO2018 / 067546; the entire contents of which are hereby incorporated by reference in their entirety. The ARRDC1 / TSG101 interaction results in the relocation of TSG101 from endosomes to the plasma membrane and mediates the release of microvesicles that contain TSG101, ARRDC1, and other cellular components as well as the molecule of interest. Molecules of interest, whether naturally or non-naturally, occurring include, but are not limited to, proteins, nucleic acids, and small molecules that can preferably associate with one or more ARMM related proteins (e.g., ARRDC1), or can be modified to associate with more specifically, TSG101 or ARRDC1 or specific motif(s) therein. These associations facilitate the incorporation of the molecules into ARMMs, which in turn can be used to deliver the desired payload (molecule of interest) into a targeted cell. By way of example, but not limitation, a payload RNA can be fused to a trans-activation response (TAR) element, thereby allowing it to associate with an ARRDC1 protein that is fused to an RNA binding protein, such as a Tat protein (e.g., bovine TAT protein). Alternatively, a payload protein can be fused to one or more WW domains, which associate with the PPXY motif of ARRDC1. The association of the molecule to an ARMM-related protein (e.g., ARRDC1), facilitates the loading of the molecule into the ARRDC1-containing ARMM. Alternatively, the molecule can be fused to an ARMM protein (e.g., TSG101 or ARRDC1) to load the payload into the ARMM. The molecule can be fused to the ARMM protein (e.g., TSG101 or ARRDC1) via a linker that may be cleaved upon delivery to a target cell. As an example, the delivery platform of ARMMs will enable multiple cis- acting structural elements of mRNAs to perform in the context of intracellular and secreted therapeutics for target cells, where these structural elements include, but are not limited to: (i) 5' cap structure; (ii) 5′ untranslated region (UTR); (iii) the codon optimized coding sequence; (iv) 3′ UTR; (v) a 3' poly-A tail consisting of a stretch of repeated adenine nucleotides; and (vi) inclusion of cis-acting zip code elements within RNA transcripts that are recognized by specific RNA binding proteins to cause specific cellular localization (e.g., to synapse of neurons). (See, e.g., Chin A., Lécuyer E., “RNA localization: Making its way to the center stage,” Biochim. Biophys. Acta. Gen Subj., 1861(11 Pt B):2956-2970 (2017)). Attorney Docket No.54926-0014WO1 As another example, the delivery platform for ARMMs will enable multiple classes of protein and mRNA-based therapeutics to be directed to target cells (e.g., phagocytes, e.g., macrophages). In some aspects of this invention, arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicles (ARMMs) containing a lipid bilayer and an ARRDC1 protein, a molecule (e.g., therapeutic agent(s)) are provided. In some aspects of the invention, microvesicle-producing cells containing a recombinant expression construct encoding an ARRDC1 protein or a variant thereof under the control of a heterologous promoter. In some additional aspects of the invention, methods of delivering a molecule (e.g., one or more therapeutic agents) to a target cell type, tissue, or structure (e.g., phagocytes, e.g., macrophages) by contacting the target with a microvesicle, as described herein, are provided. In some aspects of the invention, methods of treating a disorder in a patient by administering to the patient a microvesicle or a microvesicle-producing cell as described herein are provided. In yet other aspects, the disorder impacts the function of the immune system. In still other aspects, the disorder impacts the expression and / or function of one or more of NLRP3, IRF-5, GSDMD, ASC, STING , IL-12, IL- 10, TNF-alpha, IL-6, MCP-1, IL-33, TGF-beta, IL-27, GM-CSF, PU.1, PPARgamma, NOS, Lipoxin A4, CD86, and CD80. In other aspects of the invention, the disorder is either a gain-of-function disorder, a loss-of-function disorder, or a repeat expansion. In still other aspects of the invention, the disorder results from one or more substitutions (e.g., missense or nonsense), insertions, deletions, deletion-insertions, duplications, inversions, frameshifts, or repeat expansions. Provided herein are arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM)s, comprising: a lipid bilayer and an ARDDC1 protein, fragment thereof, or variant thereof; and a payload capable of modulating the sequence or expression of an inflammatory gene target. Also provided herein are microvesicle producing cell(s) comprising: nucleic acid construct(s) encoding: an ARRDC1 protein, fragment thereof, or variant thereof; and a payload capable of modulating the sequence or expression of an inflammatory gene target. Also provided herein are methods comprising administering an arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), Attorney Docket No.54926-0014WO1 comprising a payload capable of modulating the sequence or expression of an inflammatory gene target to a cell. Also provided herein are methods for inhibiting cyotkine release in a cell, the method comprising administering an arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising a payload capable of modulating the sequence or expression of an inflammatory gene target to a cell. Also provided herein are methods for reducing inflammation in a cell, the method comprising administering an arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising a payload capable of modulating the sequence or expression of an inflammatory gene target to a cell. Also provided herein are methods for modulating the sequence or expression of an inflammatory gene target in the cell of a subject, the method comprising administering an arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising a payload capable of modulating the sequence or expression of an inflammatory gene target. In some embodiments, wherein the cell is a phagocyte. In some embodiments the cell is a macrophage. In some embodiments the macrophage is an alveolar macrophage. In some embodiments the cell is the cell of a subject, and the method comprises administering the ARMM intranasally. Also provided herein are methods for treating a disorder associated with mutation or dysregulation of an inflammatory gene target, the method comprising administering an arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising a payload capable of modulating the sequence or expression of an inflammatory gene target to a subject in need thereof. In some embodiments, the disorder is selected from Allergic asthma, allergic rhinitis, chronic rhinosinusitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, atopic dermatitis, eosinophilic pneumonia, Crohn's disease, ulcerative colitis, psoriasis, rheumatoid arthritis (RA), primary Sjogren's syndrome, systemic sclerosis, gout, ankylosing spondylitis, pustular psoriasis, systemic lupus erythematosus (SLE), adult-onset Still's disease, Bechet’s disease, IgG4-related disease, cancer, MS, type1 diabetes, Sjogren's syndrome, atherosclerosis, acute respiratory distress syndrome (ARDS), acute lung injury, migraine, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, ischemic heart disease, diabetes, Attorney Docket No.54926-0014WO1 insulin-resistant diabetes, COVID-19, osteoarthritis, osteoporosis, ischemia-related neuronal death, excitotoxic neuronal injury, diabetes mellitus, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, lupus erythematosus, primary biliary cholangitis, Sjögren's syndrome, steroid-resistant asthma, allergic contact dermatitis, non-atopic eczema, dyslipidemia, diabetes, traumatic brain injury, ALS, Familiar cold-associated autoinflammatory syndrome, Muckle-Wells syndrome, urate crystal- induced peritonitis, acute myocardial infarction, psoriasis-like dermatitis, diabetic nephropathy, Stargardt disease type 1, atrial fibrillation, acute liver injury, nonalcoholic steatohepatitis (NASH), cirrhosis, cystic fibrosis, rheumatoid arthritis, celiac disease, asymmetrical septal hypertrophy (ASH), Silicosis, ischemia reperfusion, smoke / chemical injury, metal overload syndromes, Metabolic syndrome, type 2 diabetes, peripheral artery disease, renal disease, ulcerative colitis, myocardial ischemia / reperfusion injury, myocarditis, renal ischemia / reperfusion injury, renal fibrosis, diabetic kidney disease, periodontal disease, Minimal change disease, focal segmental glomerulosclerosis, graft-versus-host disease, polyarticular juvenile idiopathic arthritis, Hashimoto's thyroiditis, Grave's disease, Addison's disease, myasthenia gravis, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, polymyositis, scleroderma, Pulmonary alveolar proteinosis, interstitial lung disease, aortic aneurysm, obesity, axial spondyloarthritis, myelofibrosis, liver fibrosis, skin fibrosis, idiopathic pulmonary fibrosis, juvenile idiopathic arthritis, noninfectious uveitis, adult-onset Still's disease, giant cell arteritis, Takayasu arteritis, Castleman disease, cytokine release syndrome, uveitis, thyroid eye disease, erosive hand osteoarthritis, schizophrenia, Schnitzler syndrome, myocardial infarction, familiar Mediterranean fever, COVID-19 pneumonia, systemic scleroderma, myositis, pulmonary fibrosis, Aicardi-Goutières syndrome, COPA syndrome, and combinations thereof. In some embodiments, the payload comprises a ribonucleoprotein. In some embodiments, the ribonucleoprotein comprises a nuclease, optionally a Cas9 nuclease, and a gRNA. In some embodiments, the ribonucleoprotein is capable of knocking out or knocking down the expression of the inflammatory gene target. Attorney Docket No.54926-0014WO1 In some embodiments, the inflammatory gene target is NLRP3, and the ribonucleoprotein is capable of introducing a loss of function mutation in promoter region and / or exon region. In some embodiments, the gRNA comprises a spacer region comprising any one of SEQ ID NOs: 1–34. In some embodiments, the treatment target is NLRP3, the disorder is selected from familiar cold-associated autoinflammatory syndrome, Muckle-Wells syndrome, urate crystal-induced peritonitis, acute myocardial infarction, gout, psoriasis-like dermatitis, diabetic nephropathy, SLE, Stargardt disease type 1, Alzheimer's disease, atherosclerosis, atrial fibrillation, osteoarthritis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, cystic fibrosis, rheumatoid arthritis, ARDS, celiac disease, ASH, Silicosis, ischemia reperfusion, smoke / chemical injury, metal overload syndromes, and combinations thereof. In some embodiments, the treatment target is IRF-5, the disorder is selected from Sjogren's syndrome, rheumatoid arthritis, SLE, systemic scleroderma, multiple sclerosis, myositis, ulcerative colitis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, ARDS, and combinations thereof. In some embodiments, the treatment target is GSDMD, the disorder is selected from Familiar cold-associated autoinflammatory syndrome, Muckle-Wells syndrome, urate crystal-induced peritonitis, acute myocardial infarction, gout, psoriasis-like dermatitis, diabetic nephropathy, SLE, Stargardt disease type 1, Alzheimer's disease, atherosclerosis, atrial fibrillation, osteoarthritis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, cystic fibrosis, rheumatoid arthritis, ARDS, celiac disease, ASH, Silicosis, ischemia reperfusion, smoke / chemical injury, metal overload syndromes, and combinations thereof. In some embodiments, the treatment target is ASC, the disorder is selected from Familiar cold-associated autoinflammatory syndrome, Muckle-Wells syndrome, urate crystal-induced peritonitis, acute myocardial infarction, gout, psoriasis-like dermatitis, diabetic nephropathy, SLE, Stargardt disease type 1, Alzheimer's disease, atherosclerosis, atrial fibrillation, osteoarthritis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, cystic fibrosis, rheumatoid arthritis, ARDS, celiac disease, ASH, Silicosis, ischemia reperfusion, smoke / chemical injury, metal overload syndromes, and combinations thereof. Attorney Docket No.54926-0014WO1 In some embodiments, the treatment target is STING, the disorder is selected from SLE, Aicardi-Goutières syndrome, COPA syndrome, Alzheimer disease, Parkinson disease, ALS, and combinations thereof. In some embodiments, the treatment target is IL-12, the disorder is selected from Crohn's disease, ulcerative colitis, psoriasis, diabetes mellitus, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, lupus erythematosus, primary biliary cholangitis, Sjögren's syndrome, and combinations thereof. In some embodiments, the treatment target is IL-10, the disorder is selected from Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, allergic asthma, steroid-resistant asthma, allergic contact dermatitis, non-atopic eczema, dyslipidemia, diabetes, atherosclerosis, MS, traumatic brain injury, ALS, Alzheimer's disease, Parkinson's disease, and combinations thereof. In some embodiments, the treatment target is TNF-alpha, the disorder is selected from Rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis, psoriasis, noninfectious uveitis, ankylosing spondylitis, and combinations thereof. In some embodiments, the treatment target is IL-6, the disorder is selected from Rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, giant cell arteritis, Takayasu arteritis, Castleman disease, SLE, systemic sclerosis, cytokine release syndrome, uveitis, thyroid eye disease, erosive hand osteoarthritis, schizophrenia, Schnitzler syndrome, myocardial infarction, familiar Mediterranean fever, COVID-19 pneumonia, and combinations thereof. In some embodiments, the treatment target is MCP-1, the disorder is selected from Alzheimer's disease, Parkinson's disease, epilepsy, MS, atherosclerosis, stroke, ischemic heart disease diabetes, insulin-resistant diabetes, COVID-19, osteoarthritis, RA, osteoporosis, allergic asthma, ischemia-related neuronal death, exitotoxic neuronal injury, and combinations thereof. In some embodiments, the treatment target is IL-33, the disorder is selected from Allergic asthma, allergic rhinitis, chronic rhinosinusitis, COPD, pulmonary fibrosis, atopic dermatitis, eosinophilic pneumonia, Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, RA, primary Sjogren's syndrome, systemic sclerosis, gout, ankylosing spondylitis, pustular psoriasis, SLE, adult-onset Still's disease, Behcet's disease, IgG4-related disease, and combinations thereof. Attorney Docket No.54926-0014WO1 In some embodiments, the treatment target is TGF-beta, the disorder is selected from Pulmonary fibrosis, myelofibrosis, liver fibrosis, NASH, skin fibrosis, renal fibrosis, idiopathic pulmonary fibrosis, cancer, and combinations thereof. In some embodiments, the treatment target is IL-27, the disorder is selected from Allergic asthma, allergic rhinitis, cancer, MS, type 1 diabetes, Sjogren's syndrome, Crohn's disease, ulcerative colitis, atherosclerosis, and combinations thereof. In some embodiments, the treatment target is GM-CSF, the disorder is selected from Pulmonary alveolar proteinosis, RA, osteoarthritis, MS, Crohn's disease, ulcerative colitis, interstitial lung disease, aortic aneurysm, allergic asthma, obesity, COVID-19, psoriasis, axial spondylarthritis, ankylosing spondylitis, and combinations thereof. In some embodiments, the treatment target is PU.1, the disorder is selected from Pulmonary alveolar proteinosis, Grave's disease, Hashimoto's thyroiditis, MS, RA, psoriatic arthritis, psoriasis, systemic sclerosis, SLE, Sjogren's syndrome, primary biliary cirrhosis, type 2 diabetes, Alzheimer's disease, Parkinson's disease, allergic asthma, and combinations thereof. In some embodiments, the treatment target is PPARgamma, the disorder is selected from Pulmonary alveolar proteinosis, Grave's disease, Hashimoto's thyroiditis, MS, RA, psoriatic arthritis, psoriasis, systemic sclerosis, SLE, Sjogren's syndrome, primary biliary cirrhosis, type 2 diabetes, Alzheimer's disease, Parkinson's disease, allergic asthma, and combinations thereof. In some embodiments, the treatment target is NOS, the disorder is selected from Allergic asthma, ARDS, acute lung injury, RA, Alzheimer's, Parkinson's, pulmonary fibrosis, atherosclerosis, migraine, and combinations thereof. In some embodiments, the treatment target is Lipoxin A4, the disorder is selected from Metabolic syndrome, type 2 diabetes, peripheral artery disease, renal disease, COPD, Crohn's disease, ulerative colitis, RA, cancer, Alzheimer's disease, stroke, atherosclerosis, myocardial ischemia / reperfusion injury, myocarditis, acute lung injury, allergic asthma, pulmonary fibrosis, cystic fibrosis, renal ischemia / reperfusion injury, renal fibrosis, diabetic kidney disease, periodontal disease, and combinations thereof. In some embodiments, the treatment target is CD86, the disorder is selected from Minimal change disease, focal segmental glomerulosclerosis, psoriasis, psoriatic Attorney Docket No.54926-0014WO1 arthritis, RA, graft-versus-host disease, polyarticular juvenile idiopathic arthritis, type 1 diabetes, MS, SLE, Hashimoto's thyroiditis, Grave's disease, Addison's disease, Crohn's disease, ulcerative colitis, myastenia gravis, sympathetic ophtalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, Sjogren's syndrome, polymyositis, scleroderma, and combinations thereof. In some embodiments, the treatment target is CD80, the disorder is selected from Minimal change disease, focal segmental glomerulosclerosis, psoriasis, psoriatic arthritis, RA, graft-versus-host disease, polyarticular juvenile idiopathic arthritis, type 1 diabetes, MS, SLE, Hashimoto's thyroiditis, Grave's disease, Addison's disease, Crohn's disease, ulcerative colitis, myastenia gravis, sympathetic ophtalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, Sjogren's syndrome, polymyositis, scleroderma, and combinations thereof. In another aspect, the disclosure provides arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicles (ARMM), comprising: a lipid bilayer and an ARDDC1 protein, fragment thereof, or variant thereof; and a payload capable of modulating the sequence or expression of an inflammatory gene target. In another aspect, the disclosure provides microvesicle producing cell comprising: nucleic acid construct(s) encoding: an ARRDC1 protein, fragment thereof, or variant thereof; and a payload capable of modulating the sequence or expression of an inflammatory gene target. In another aspect, the disclosure provides methods comprising administering an arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising a payload capable of modulating the sequence or expression of an inflammatory gene target to a cell. In another aspect, the disclosure provides methods for inhibiting cyotkine release in a cell, the method comprising administering an arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising a payload capable of modulating the sequence or expression of an inflammatory gene target to a cell. In another aspect, the disclosure provides methods for reducing inflammation in a cell, the method comprising administering an arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising a payload capable of modulating the sequence or expression of an inflammatory gene target to a cell. Attorney Docket No.54926-0014WO1 In another aspect, the disclosure provides methods for modulating the sequence or expression of an inflammatory gene target in the cell of a subject, the method comprising administering an arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising a payload capable of modulating the sequence or expression of an inflammatory gene target. In some embodiments, the cell is a phagocyte. In some embodiments, the cell is a macrophage. In some embodiments, the macrophage is an alveolar macrophage. In some embodiments, the cell is the cell of a subject, and the method comprises administering the ARMM intranasally. In some embodiments, the macrophage is a liver resident macrophage. In some embodiments, the liver resident macrophage is a Kupffer cell. In some embodiments, the gene target is NLRP3, IRF-5, GSDMD, ASC, STING, IL-12, IL-10, TNF-alpha, IL-6, MCP-1, IL-33, TGF-beta, IL-27, GM-CSF, PU.1, PPARgamma, NOS, Lipoxin A4, CD86, CD80, and portions, and combinations thereof. In some embodiments, the gene target is NLRP3. In another aspect, the disclosure provides methods for treating a disorder associated with mutation or dysregulation of an inflammatory gene target, the method comprising administering an arrestin domain-containing protein 1 (ARRDC1)- mediated microvesicle (ARMM), comprising a payload capable of modulating the sequence or expression of an inflammatory gene target to a subject in need thereof. In some embodiments, the microvesicle producing cell or method includes a payload comprising a ribonucleoprotein. In some embodiments, the ribonucleoprotein comprises a nuclease, optionally a Cas9 nuclease, and a gRNA. In some embodiments, the ribonucleoprotein is capable of knocking out or knocking down the expression of the inflammatory gene target. In some embodiments, the inflammatory gene target is NLRP3, and the ribonucleoprotein is capable of introducing a loss of function mutation in promoter region and / or exon region. In some embodiments, the inflammatory gene target is NLRP3, and wherein the gRNA comprises a sequence selected from any one of SEQ ID NOs: 1-34 and 92-114. In some embodiments, the gRNA comprises a spacer region targeting the promoter region of NLRP3. In some embodiments, the spacer region comprises or consists of the nucleic acid sequence of any one of SEQ ID NOs: 9 and 10. Attorney Docket No.54926-0014WO1 In some embodiments, the gRNA comprises a spacer region targeting an exon of NLRP3. In some embodiments, the spacer region comprises or consists of the nucleic acid sequence of any one of SEQ ID NOs: 97, 100, 101, 106, and 112. In some embodiments, the subject is experiencing inflammation of one or more tissues. In some embodiments, the subject is experiencing inflammation of liver tissue. In some embodiments, the subject has acute liver injury. In some embodiments, the subject is experiencing inflammation of lung tissue. In some embodiments, the subject has acute lung injury. In some embodiments, the subject has interstitial lung disease. In some embodiments, the administration is intravenous administration. In some embodiments, the administration is by inhalation. Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof. The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of” can include determining the amount of something present in addition to determining whether it is present or absent depending on the context. As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value. Attorney Docket No.54926-0014WO1 Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. DEFINITIONS The terms “ARRDC1-mediated microvesicle” or “ARMM,” as used herein, refers to a microvesicle comprising an ARRDC1 protein or variant thereof, and / or TSG101 protein, or variant thereof. ARMMs have been described in detail, for example, in PCT application number PCT / US2013 / 024839, filed February 6, 2013 (published as WO 2013 / 119602 A1 on August 15, 2013) by Lu et al., and entitled “Arrdc1-Mediated Microvesicles (ARMMs) and Uses Thereof,” as well as in U.S. Pat Nos.9,737,480; 9,816,080; 10,260,055, 10,945,954, 11,001,817, and PCT Publications WO2018 / 067546, WO2021 / 062196, and WO2021 / 252924; the entire contents of which are hereby incorporated by reference in their entirety. In some embodiments, the ARMM is shed from a cell (e.g., producer cell), and comprises an agent (payload), for example, a nucleic acid, protein, or small molecule, present in the cytoplasm or associated with the membrane of the cell. Exemplary payloads include, but are not limited to a nucleic acid, protein, or small molecule, present in the cytoplasm or associated with the membrane of the cell. In some embodiments, the ARMM is shed from a cell (e.g., a transgenic cell), and comprises an agent, for example, a nucleic acid, protein, or small molecule, present in the cytoplasm or associated with the membrane of the cell. In some embodiments, the ARMM is shed from a transgenic cell comprising a recombinant expression construct that includes a transgene, and the ARMM comprises a gene product, for example, an RNA transcript and / or a protein (e.g., an ARRDC1-Tat fusion protein and a TAR- payload RNA) Attorney Docket No.54926-0014WO1 encoded by the expression construct. In some embodiments, the ARMM is produced synthetically, for example, by contacting a lipid bilayer with an ARRDC1 protein or a variant thereof, or a variant thereof, in a cell-free system in the presence of TSG101, or a variant thereof. In other embodiments, the ARMM is synthetically produced by contacting a lipid bilayer with HECT domain ligase, and VPS4a. In some embodiments, an ARMM lacks a late endosomal marker. Some of the ARMMs provided herein do not include, or are negative for, one or more exosomal biomarkers. Exosomal biomarkers are known to those of skill in the art and include, but are not limited to, CD63, Lamp-1, Lamp-2, CD9, HSPA8, GAPDH, CD81, SDCBP, PDCD6IP, ENO1, ANXA2, ACTB, YWHAZ, HSP90AA1, ANXA5, EEF1A1, YWHAE, PPIA, MSN, CFL1, ALDOA, PGK1, EEF2, ANXA1, PKM2, HLA-DRA, and YWHAB. Certain ARMMs provided herein may include an exosomal biomarker. Accordingly, some ARMMs may be negative for one or more other exosomal biomarkers, but positive for one or more different exosomal biomarkers. For example, such an ARMM may be negative for CD63 and Lamp-1 but may include PGK1 or GAPDH; or may be negative for CD63, Lamp-1, CD9, and CD81, but may be positive for HLA-DRA. In some embodiments, ARMMs include an exosomal biomarker, but at a lower level than the level found in exosomes. For example, some ARMMs include one or more exosomal biomarkers at a level of less than about 1%, less than about 5%, less than about 10%, less than about 20%, less than about 30%, less than about 40%, or less than about 50% of the level of that biomarker found in exosomes. To give a non-limiting example, in some embodiments, an ARMM may be negative for CD63 and Lamp-1, include CD9 at a level of less than about 5% of the level of CD9 typically found in exosomes, and be positive for ACTB. Exosomal biomarkers in addition to those listed above are known in the art, and the invention is not limited in this regard. The term “cargo protein,” as used herein, refers to a protein that may be incorporated in an ARMM, for example, into the liquid phase of the ARMM or into the lipid bilayer of an ARMM. The term “cargo protein to be delivered” refers to any protein that can be delivered via its association with or inclusion in an ARMM to a subject, organ (e.g., liver, kidneys, heart, pancreas, brain, etc.), tissue, or cell. In some embodiments, the cargo protein is to be delivered to a target cell in vitro, in vivo, or ex vivo. In some embodiments, the cargo protein to be delivered is a biologically active agent, i.e., it has activity in a cell, organ, tissue, and / or subject. For instance, a protein Attorney Docket No.54926-0014WO1 that, when administered to a subject, has a biological effect on that subject, is considered biologically active. In certain embodiments, the cargo protein is an RNA binding protein (“RNB”), In some cases, the RNA binding protein is or comprises a Cas protein or variant thereof (e.g., a Cas protein (e.g., Cas9, C2c1, Cpf1, Cas12a, Cas13, Cas14) or variant thereof. In some cases, the RNA binding protein is or comprises a nuclease protein or variant thereof. In certain embodiments, the nuclease may be a Cas9 nuclease, a TALE nuclease, a zinc finger nuclease, or any variant thereof. Nucleases, including Cas9 proteins and their variants, are described in more detail elsewhere herein. In some embodiments, the Cas9 protein or variant thereof is associated with nucleic acid. For example, the cargo protein may be a Cas9 protein associated with a gRNA (e.g., as a ribonucleoprotein “RNP”). In some embodiments, a cargo protein to be delivered is a therapeutic agent. As used herein, the term “therapeutic agent” refers to any agent that, when administered to a subject has a beneficial effect. In some embodiments, the therapeutic agent comprises a small molecule, a protein (or peptide), one or more nucleic acids, or an agent associated with a small molecule. In some embodiments, the payload to be delivered is a diagnostic agent. In some embodiments, the agent to be delivered is a prophylactic agent. In some embodiments, the agent to be delivered is useful as an imaging agent. In some of these embodiments, the diagnostic or imaging agent is, and in others, it is not, biologically active. In some embodiments, the therapeutic agent comprises an agent that reduces (knocks down) the expression of one or more genes in an organism (e.g., a subject). In other embodiments, the therapeutic agent comprises an agent that inactivates or removes (knocks out) one or more specific genes in an organism (e.g., a subject). In some embodiments, the therapeutic agent to be delivered to a cell is a transcription factor, a tumor suppressor, a developmental regulator, a growth factor, a metastasis suppressor, a pro-apoptotic protein, a nuclease, or a recombinase. As used herein, the term “therapeutic effect” refers to a consequence of treatment, the results of which are judged to be desirable and beneficial. A therapeutic effect can include, directly or indirectly, the arrest, reduction, or elimination of a disease manifestation. A therapeutic effect can also include, directly or indirectly, the arrest reduction or elimination of the progression of a disease manifestation. As used herein, the term “transcription factor” refers to a DNA-binding protein that regulates the transcription of DNA into RNA, for example, by activation Attorney Docket No.54926-0014WO1 or repression of transcription. Some transcription factors affect the regulation of transcription alone, while others act in concert with other proteins. Some transcription factors can both activate and repress transcription under certain conditions. In general, transcription factors bind a specific target sequence or sequences highly similar to a specific consensus sequence in a regulatory region of a target gene. Transcription factors may regulate the transcription of a target gene alone or in a complex with other molecules. Examples of transcription factors include, but are not limited to, Sp1, NF1, CCAAT, GATA, HNF, PIT-1, MyoD, Myf5, Hox, Winged Helix, SREBP, p53, CREB, AP-1, Mef2, STAT, R-SMAD, NF-Κβ, Notch, TUBBY, and NFAT. The term “binding RNA,” as used herein, refers to a ribonucleic acid (RNA) that binds to an RNA binding protein, for example, any of the RNA binding proteins known in the art and / or described herein. In some embodiments, a binding RNA is an RNA that specifically binds to an RNA binding protein. A binding RNA that “specifically binds” to an RNA binding protein, binds to the RNA binding protein with greater affinity, avidity, more readily, and / or with greater duration than it binds to another protein, such as a protein that does not bind the RNA or a protein that weakly binds to the binding RNA. In some embodiments, the binding RNA is a naturally occurring RNA, or non-naturally occurring variant thereof, that binds to a specific RNA binding protein. For example, the binding RNA may be a TAR element, a Rev response element, an MS2 RNA, or any variant thereof that specifically binds an RNA binding protein. In some embodiments, the binding RNA may be a trans- activating response element (TAR element), or variant thereof, which is an RNA stem-loop structure that is found at the 5ʹ-ends of nascent HIV-1 transcripts and specifically binds to the trans-activator of transcription (Tat) protein. In some embodiments, the binding RNA is a Rev response element (RRE), or variant thereof, that specifically binds to the accessory protein Rev (e.g., Rev from HIV-1). In some embodiments, the binding RNA is an MS2 RNA that specifically binds to a MS2 phage coat protein. The binding RNAs of the present disclosure may be designed to specifically bind a protein (e.g., an RNA binding protein fused to ARRDC1) to facilitate loading of the binding RNA (e.g., a binding RNA fused to a payload RNA) into an ARMM. The term “aptamer,” as used herein, refers to nucleic acids (e.g., RNA, DNA) that bind to a specific target molecule, e.g., an RNA binding protein. In some embodiments, nucleic acid (e.g., DNA or RNA) aptamers are engineered through Attorney Docket No.54926-0014WO1 repeated rounds of in vitro selection or alternatively, SELEX (systematic evolution of ligands by exponential enrichment) methodology, to bind to various molecular targets, for example, proteins, small molecules, macromolecules, metabolites, carbohydrates, metals, nucleic acids, cells, tissues, and organisms. Methods for engineering aptamers to bind to various molecular targets, such as proteins, are known in the art and include those described in U.S. Pat. Nos.6,376,19; and 9,061,043; Shui, B., et al., “RNA aptamers that functionally interact with green fluorescent protein and its derivatives,” Nucleic Acids Res., Mar; 40(5): e39 (2012); Trujillo, U.H., et al., “DNA and RNA aptamers: from tools for basic research towards therapeutic applications,” Comb. Chem. High Throughput Screen, 9(8):619–32 (2006); Srisawat, C., et al., “Streptavidin aptamers: Affinity tags for the study of RNAs and ribonucleoproteins,” RNA, 7:632–641 (2001); and Tuerk and Gold, “Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase,” Science, (1990); the entire contents of each of which are hereby incorporated by reference in their entirety. The term “RNA binding protein,” as used herein, refers to a polypeptide molecule that binds to a binding RNA, for example, any of the binding RNAs known in the art and / or described herein. In some embodiments, an RNA binding protein is a protein that specifically binds to a binding RNA. An RNA binding protein that “specifically binds” to a binding RNA, binds to the binding RNA with greater affinity, avidity, more readily, and / or with greater duration than it binds to another RNA, such as a control RNA (e.g., an RNA having a random nucleic acid sequence) or an RNA that weakly binds to the RNA binding protein. In some embodiments, the RNA binding protein is a naturally occurring protein or a non-naturally occurring variant thereof, that binds to a specific RNA. For example, in some embodiments, the RNA binding protein may be a trans-activator of transcription (Tat) protein that specifically binds a trans-activating response element (TAR element). In some embodiments, the Tat protein is from a bovine. In some embodiments, the RNA binding protein is a regulator of virion expression (Rev) protein (e.g., Rev from HIV- 1) or variant thereof, that specifically binds to a Rev response element (RRE). In some embodiments, the RNA binding protein is a coat protein of an MS2 bacteriophage that specifically binds to an MS2 RNA. The RNA binding proteins useful in the present disclosure (e.g., a binding protein fused to ARRDC1) may be designed to specifically Attorney Docket No.54926-0014WO1 bind a binding RNA (e.g., a binding RNA fused to a payload RNA) to facilitate loading of the binding RNA into an ARMM. The term “payload,” “payload protein,” “payload nucleic acid,” “payload DNA,” “payload RNA,” or “payload small molecule,” as used herein, refers to a protein, nucleic acid, including DNA or RNA, or a small molecule, respectively, that may be incorporated into an ARMM, for example, into the liquid phase of the ARMM or into the lipid bilayer of an ARMM. Types of payload protein, payload nucleic acid, payload DNA, payload RNA, and payload small molecule are known in the art and include those described in U.S. Pat. Nos.: 9,737,480; 9,816,080; 10,260,055; and PCT Publication WO2018 / 067546; the entire contents of each of which are hereby incorporated by reference in their entirety. In some cases, the payload is a cargo protein or peptide (e.g., as described herein). The payload can be delivered via its association with or inclusion in an ARMM to a subject, organ, tissue, or cell. In some embodiments, the payload is to be delivered to a targeted cell in vitro, in vivo, or ex vivo. In some embodiments, the payload to be delivered is a biologically active agent, i.e., it has activity in a cell, organ, tissue, and / or subject. For instance, a protein, nucleic acid (e.g., DNA or RNA), or small molecule that, when administered to a subject, has a biological effect on that subject or is biologically active. In some embodiments, a payload to be delivered is a therapeutic agent. The term “linker,” as used herein, refers to a chemical moiety linking two molecules or moieties, e.g., an ARRDC1 protein and a Tat protein, a WW domain, and a Tat protein, or an ARRDC1 protein and a Cas9 nuclease. Typically, the linker is positioned between, or flanked by, two groups, molecules, or other moieties and connected to each one via a covalent bond, thus connecting the two. In some embodiments, the linker comprises an amino acid or a plurality of amino acids (e.g., a peptide or protein). In some embodiments, the linker comprises a nucleotide (e.g., DNA or RNA) or a plurality of nucleotides (e.g., a nucleic acid). In some embodiments, the linker is an organic molecule, functional group, polymer, or other chemical moiety / moieties. In some embodiments, the linker is a cleavable linker, e.g., the linker comprises a bond that can be cleaved upon exposure to, for example, UV light or a hydrolytic enzyme, such as a protease or esterase. In some embodiments, the linker is any stretch of amino acids having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20, at Attorney Docket No.54926-0014WO1 least 25, at least 30, at least 40, at least 50, or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 amino acids). In other embodiments, the linker is a chemical bond (e.g., a covalent bond, amide bond, disulfide bond, ester bond, carbon-carbon bond, carbon-heteroatom bond, and the like). As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, the term “animal” refers to a human of either sex at any stage of development. In some embodiments, the term “animal” refers to a non- human animal at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). Animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and worms. In some embodiments, the animal is a transgenic animal, a genetically engineered animal, or a clone. In some embodiments, the animal is a transgenic non-human animal, a genetically engineered non-human animal, or a non-human clone. As used herein, the terms “associated with,” “conjugated,” “linked,” “attached,” and the like, when used with respect to two or more entities, for example, with chemical moieties, molecules, and / or ARMMs, means that the entities are physically associated or connected with one another, either directly or via one or more additional moieties that serve as a linker, to form a structure that is sufficiently stable so that the entities remain physically associated under the conditions in which the structure is used, e.g., under physiological conditions. An ARMM microvesicle is typically associated with an agent, for example, a nucleic acid, protein, or small molecule, by a mechanism that involves a covalent (e.g., via an amide bond) or non- covalent association (e.g., between ARRDC1 and a WW domain, or between a Tat protein and a TAR element). In certain embodiments, the agent (e.g., a therapeutic agent, a payload protein, payload nucleic acid, or payload small molecule) is covalently bound to a molecule that associates non-covalently with a part of the ARMM that is fused to an ARRCD1 protein, a TSG101 protein or variant thereof, or a lipid bilayer-associated protein by a covalent bond (e.g., an amide bond), or variant thereof. In some embodiments, the association is via a linker, for example, a cleavable linker. In some embodiments, an entity (e.g., a payload protein, payload nucleic acid, or payload small molecule) is associated with an ARMM by inclusion in the ARMM, Attorney Docket No.54926-0014WO1 for example, by encapsulation of the molecule within the ARMM. For example, in some embodiments, a molecule (e.g., a therapeutic agent, a payload protein, payload nucleic acid, or payload small molecule) present in the cytoplasm of an ARMM- producing cell is associated with an ARMM by encapsulation of the cytoplasm with the agent in the ARMM upon ARMM budding. Similarly, a membrane protein or other molecule associated with the cell membrane of an ARMM producing cell may be associated with an ARMM produced by the cell by inclusion into the ARMM’s membrane upon budding. As used herein, the phrase “biologically active” refers to a characteristic of any substance that has activity in a cell, organ, tissue, and / or subject. For instance, a substance that when administered to an organism produces or elicits a biological effect on that organism is biologically active. As one example, a payload RNA may be considered biologically active if it increases or decreases the expression of a gene product when administered to a subject or cell. As another example, a nuclease payload protein may be considered biologically active if it increases or decreases the expression of a gene product when administered to a subject. As used herein, the term “conserved” refers to nucleotides or amino acid residues of a polynucleotide sequence or amino acid sequence, respectively, that are those that occur unaltered in the same position of two or more related sequences being compared. Nucleotides or amino acids that are relatively conserved are those that are conserved amongst more related sequences than nucleotides or amino acids appearing elsewhere in the sequences. In some embodiments, two or more sequences are said to be “completely conserved” if they are 100% identical to one another. In some embodiments, two or more sequences are said to be “highly conserved” if they are at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some embodiments, two or more sequences are said to be “highly conserved” if they are about 70% identical, about 80% identical, about 90% identical, about 95% identical, about 98% identical, or about 99% identical to one another. In some embodiments, two or more sequences are said to be “conserved” if they are at least 30% identical, at least 40% identical, at least 50% identical, at least 60% identical, at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some embodiments, two or more sequences are said to be “conserved” if they are about 30% identical, about 40% identical, about 50% identical, about 60% identical, about 70% identical, about 80% identical, about Attorney Docket No.54926-0014WO1 90% identical, about 95% identical, about 98% identical, or about 99% identical to one another. The term “engineered,” as used herein, refers to a protein, nucleic acid, complex, substance, or entity that has been designed, produced, prepared, synthesized, and / or manufactured by a human. Accordingly, an engineered product is a product that does not occur in nature. In some embodiments, an engineered protein or nucleic acid is a protein or nucleic acid that has been designed to meet requirements or to have desired features. For example, a payload RNA may be engineered to associate with the ARRDC1 by fusing one or more WW domains to a Tat protein and fusing the payload RNA to a TAR element to facilitate loading of the payload RNA into an ARMM. As another example, a payload RNA may be engineered to associate with the ARRDC1 by fusing a Tat protein to the ARRDC1 and by fusing the payload RNA to a TAR element to facilitate loading of the payload RNA into an ARMM. As another example, a payload protein may be engineered to associate with the ARRDC1 by fusing one or more WW domains to the payload protein to facilitate the loading of the payload protein into an ARMM. As used herein, the term “expression” of a nucleic acid sequence refers to one or more of the following events: (1) production of an RNA transcript from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, 5′ cap formation, and / or 3′ end processing); (3) translation of an RNA transcript into a polypeptide or protein; and (4) post-translational modification of a polypeptide or protein. The term “operably linked,” as used herein, refers to an arrangement of sequences or regions wherein the components are configured to perform their usual or intended function. Thus, a regulatory or control sequence operably linked to a coding sequence is capable of affecting the expression of the coding sequence. The regulatory or control sequences need not be contiguous with the coding sequence, so long as they function to direct the proper expression or polypeptide production. Thus, for example, intervening untranslated but transcribed sequences can be present between a promoter sequence and the coding sequence and the promoter sequence can still be considered operably linked to the coding sequence. A promoter sequence, as described herein, is a DNA regulatory region a short distance from the 5′ end of a gene that acts as the binding site for RNA polymerase. The promoter sequence may bind RNA polymerase in a cell and / or initiate transcription of a downstream (3′ Attorney Docket No.54926-0014WO1 direction) coding sequence. The promoter sequence may be a promoter capable of initiating transcription in prokaryotes or eukaryotes. Some non-limiting examples of eukaryotic promoters include the cytomegalovirus (CMV) promoter, the chicken β- actin (CBA) promoter, and a hybrid form of the CBA promoter (CBh). As used herein, a “fusion protein” includes a first protein moiety, e.g., an ARRCD1 protein or variant thereof, or a TSG101 protein or variant thereof, associated with a second protein moiety, for example, a protein to be delivered to a target cell through a peptide linkage. In certain embodiments, the fusion protein is encoded by a single fusion gene. As used herein, the term “gene” has its meaning as understood in the art. It will be appreciated by those of ordinary skill in the art that the term “gene” may include gene regulatory sequences (e.g., promoters, enhancers, etc.) and / or intron sequences. It will further be appreciated that the definition of a gene includes references to nucleic acids that do not encode proteins but rather encode functional RNA molecules, such as gRNAs, RNAi agents, ribozymes, tRNAs, etc. It should be noted that, as used in the present application, the term “gene” generally refers to a portion of a nucleic acid that encodes a protein; the term may optionally encompass regulatory sequences, as will be clear from context to those of ordinary skill in the art. This definition is not intended to exclude the application of the term “gene” to non- protein–coding expression units but rather to clarify that, in most cases, the term as used herein refers to a protein-coding nucleic acid. As used herein, the term “gene product” or “expression product” generally refers to an RNA transcribed from the gene (pre-and / or post-processing) or a polypeptide (pre- and / or post-modification) encoded by an RNA transcribed from the gene. As used herein, the term “green fluorescent protein” (GFP) refers to a protein originally isolated from the jellyfish Aequorea victoria that fluoresces green when exposed to blue light or a derivative of such a protein (e.g., an enhanced or wavelength-shifted version of the protein). The amino acid sequence of wild-type GFP is set forth in SEQ ID NO: 36. Proteins that are at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% homologous to SEQ ID NO: 36 are also considered to be green fluorescent proteins. As used herein, the term “homology” refers to the overall relatedness between nucleic acids (e.g., DNA molecules and / or RNA molecules) or polypeptides. In some Attorney Docket No.54926-0014WO1 embodiments, nucleic acids or proteins are considered to be “homologous” to one another if their sequences are at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical. In some embodiments, nucleic acids or proteins are considered “homologous” to one another if their sequences are at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical. The term “homologous” necessarily refers to a comparison between at least two sequences (nucleotide sequences or amino acid sequences). In accordance with the invention, two nucleotide sequences are considered homologous if the polypeptides they encode are at least about 50% identical, at least about 60% identical, at least about 70% identical, at least about 80% identical, or at least about 90% identical for at least one stretch of at least about 20 amino acids. In some embodiments, homologous nucleotide sequences are characterized by the ability to encode a stretch of at least 4–5 uniquely specified amino acids. Both the identity and the approximate spacing of these amino acids relative to one another must be considered for sequences to be considered homologous. For nucleotide sequences less than 60 nucleotides in length, homology is determined by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. In accordance with the invention, two protein sequences are considered homologous if the proteins are at least about 50% identical, at least about 60% identical, at least about 70% identical, at least about 80% identical, or at least about 90% identical for at least one stretch of at least about 20 amino acids. As used herein, the term “identity” refers to the overall relatedness between nucleic acids or proteins (e.g., DNA molecules, RNA molecules, and / or polypeptides). Calculation of the percent identity of two nucleic acid sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and second nucleic acid sequence for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that Attorney Docket No.54926-0014WO1 position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleotide sequences can be determined using methods such as those described in Computational Molecular Biology, Lesk, A.M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smth, D. W., ed., Academic Press, New York, 1993; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; each of which is incorporated herein by reference. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4:11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix. Methods commonly employed to determine percent identity between sequences include, but are not limited to those disclosed in Carillo, H., and Lipman, D., SIAM J Applied Math., 48:1073 (1988); incorporated herein by reference. Techniques for determining identity are codified in publicly available computer programs. Exemplary computer software to determine homology between two sequences include, but are not limited to, GCG program package, Devereux, J., et al., Nucleic Acids Research, 12(1), 387 (1984)), BLASTP, BLASTN, and FASTA Atschul, S.F., et al., J. Molec. Biol., 215, 403 (1990)). As used herein, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc., rather than within an organism (e.g., animal, plant, or microbe). As used herein, the term “in vivo” refers to events that occur within an organism (e.g., animal, plant, or microbe). In some embodiments, a transgene comprising a sequence encoding an ARRDC1 protein, or a portion thereof, and one or more sequences encoding a therapeutic agent, cargo protein, or nucleic acid of interest Attorney Docket No.54926-0014WO1 is administered to an animal. In some of these embodiments, the animal receiving the administered transgene is preferably a mammal, and more preferably, a human subject. As used herein, the term “ex vivo” refers to events outside of the living body and thusly is understood to refer to medical procedures in which an organ, cells, or tissue is taken from a living body for a treatment or procedure, and then returned to the same, or another, living body. In certain embodiments, ex vivo therapy comprises inducing one or more genetic modifications in a patient’s cells outside of their body to produce therapeutic effects therein and the subsequent transfer (e.g., transplantation) of the cells back into the patient. As used herein, the term “isolated” refers to a substance or entity that has been: (1) separated from at least some of the components with which it was associated when initially produced (whether in nature or in an experimental setting); and / or (2) produced, prepared, and / or manufactured by the hand of man. Isolated substances and / or entities may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were initially associated. In some embodiments, isolated substances are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. As used herein, a substance is “pure” if it is substantially free of other components. As used herein, the term “nucleic acid,” in its broadest sense, refers to a compound and / or substance that is or can be incorporated into an oligonucleotide chain via a phosphodiester linkage. In some embodiments, “nucleic acid” refers to individual nucleic acid residues (e.g., nucleotides and / or nucleosides). In some embodiments, “nucleic acid” refers to an oligonucleotide chain comprising individual nucleotides. As used herein, the terms “oligonucleotide” and “polynucleotide” can be used interchangeably to refer to a polymer of nucleotides (e.g., a string of at least two nucleotides). In some embodiments, “nucleic acid” encompasses RNA as well as single and / or double-stranded DNA and / or complementary DNA (cDNA). Furthermore, the terms “nucleic acid,” “DNA,” “RNA,” and / or similar terms include nucleic acid analogs, i.e., analogs having other than a phosphodiester backbone. For example, the so-called “peptide nucleic acids,” which are known in the art and have peptide bonds instead of phosphodiester bonds in the backbone, are considered within Attorney Docket No.54926-0014WO1 the scope of the present invention. The term “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and / or encode the same amino acid sequence. Nucleotide sequences that encode proteins and / or RNA may include introns. Nucleic acids can be purified from natural sources, produced using recombinant expression systems and optionally purified, chemically synthesized, etc. Where appropriate, e.g., in the case of chemically synthesized molecules, nucleic acids can comprise nucleoside analogs such as analogs having chemically modified bases or sugars, backbone modifications, etc. A nucleic acid sequence is presented in the 5′ to 3′ direction unless otherwise indicated. The term “nucleic acid segment” is used herein to refer to a nucleic acid sequence that is a portion of a longer nucleic acid sequence. In many embodiments, a nucleic acid segment comprises at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or more residues. In some embodiments, a nucleic acid is or comprises natural nucleosides (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine); nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo- pyrimidine, 3-methyl adenosine, 5-methylcytidine, 2-aminoadenosine, C5- bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl- cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine); chemically modified bases; biologically modified bases (e.g., methylated bases); intercalated bases; modified sugars (e.g., 2′-fluororibose, ribose, 2′-deoxyribose, arabinose, and hexose); and / or modified phosphate groups (e.g., phosphorothioates and 5′-N-phosphoramidite linkages). In some embodiments, the present invention is specifically directed to “unmodified nucleic acids,” meaning nucleic acids (e.g., polynucleotides and residues, including nucleotides and / or nucleosides) that have not been chemically modified to facilitate or achieve delivery. As used herein, the term “protein” refers to a string of at least two amino acids linked to one another by one or more peptide bonds. Proteins may include moieties other than amino acids (e.g., may be glycoproteins) and / or may be otherwise processed or modified. Those of ordinary skill in the art will appreciate that a “protein” can be a complete protein chain as produced by a cell (with or without a signal sequence) or can be a functional portion thereof. Those of ordinary skill will further appreciate that a protein can sometimes include more than one protein chain, Attorney Docket No.54926-0014WO1 for example linked by one or more disulfide bonds or associated by other means. Proteins may contain L-amino acids, D-amino acids, or both and may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, e.g., addition of a chemical entity such as a carbohydrate group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, an amide group, a terminal acetyl group, a linker for conjugation, functionalization, or other modification (e.g., alpha amidation), etc. In certain embodiments, the modifications of the protein lead to a more stable protein (e.g., greater half-life in vivo). These modifications may include cyclization of the protein, the incorporation ofD-amino acids, etc. None of the modifications should substantially interfere with the desired biological activity of the protein. In certain embodiments, the modifications of the protein lead to a more biologically active protein. In some embodiments, proteins may comprise natural amino acids, non-natural amino acids, synthetic amino acids, amino acid analogs, and combinations thereof. As used herein, the terms “subject,” or “patient” refer to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals, such as mice, rats, rabbits, production and farm animals, pets, non-human primates, and humans). In some embodiments, the subject is a patient having or suspected of having a disease or disorder. In other embodiments, the subject is a healthy volunteer. As used herein, the terms "disease," and “disorder” refer to any condition, pathological condition, or disorder that damages or interferes with the normal function of a cell, tissue, or organ. As used herein, the terms “treating,” or "treatment" refer to partially or completely preventing, altering, and / or reducing the incidence of one or more symptoms or features of a particular disease or deleterious condition. In one sense of the invention, treatments can be performed either for prophylaxis or amelioration of a pathological condition in a subject. Therapeutic effects of treatment include, without limitation, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastases, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. Treatment may be administered to a subject who does not exhibit signs or symptoms of a disease, Attorney Docket No.54926-0014WO1 disorder, condition, or to a subject who exhibits only early signs or symptoms of a disease, or condition for the purpose of decreasing the risk of developing or progressing to more severe effects associated with the disease, disorder, or condition. A treatment may prevent the onset of the disorder or a symptom of the disorder in a subject. A treatment can prevent physical deterioration (e.g., loss of vision, loss of visual acuity, low vision, blindness, decrease in ambulation, and more generally, any ameliorable morbidity) caused by a by preventing or reversing its progression. As used herein, the term “therapeutically effective amount” means an amount of an agent or payload to be delivered (e.g., nucleic acid, protein, drug, therapeutic agent, diagnostic agent, prophylactic agent, ARMM, or ARMM comprising a payload protein or payload RNA) that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, improve symptoms thereof, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. A therapeutically effective amount may be initially determined from preliminary in vitro studies and / or animal models. A therapeutically effective dose may also be determined from human data. The applied dose may be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other well-known methods is within the capabilities of the ordinarily skilled artisan. General principles for determining therapeutic effectiveness, which may be found in Chapter 1 of Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, McGraw-Hill (New York) (2001), incorporated herein by reference in its entirety. As used herein, the term "targeting ligand" refers to a ligand, or a function portion thereof, that binds to "a targeted receptor" that distinguishes the cell being targeted from other cells. The ligands may be capable of binding due to expression or preferential expression of a receptor for the ligand, accessible for ligand binding, on the target cells. Examples of such ligands include GE11 peptide, anti-EGFR nanobody, cRGD (cyclo (RGDfC), KE108 peptide, octreotide, prostate-specific membrane antigen (PSMA) aptamer, TRC105, chimeric monoclonal antibodies, tumor-specific monoclonal or polyclonal antibodies (e.g., Rituximab, Trastuzumab, Bevacizumab, Alemtuzumab, Panitumumab, etc., and bioequivalents and portions thereof), arginylglycylaspartic acid (“RGD”), DARPins, RNA aptamers, DNA aptamers, inteins, exteins, viral derived and nonviral derived cell-cell fusion protein Attorney Docket No.54926-0014WO1 (“fusogen(s)”) (e.g., VSV-G, syncytin-1, -2, HAP2, SNAREs (e.g., VAMP1, 2, 3, 4, 7, 8)), membrane proteins, such as tetraspanins (“TM4SF proteins”) (e.g., TSPAN1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, and 33, and the like), peptide ligands identified from library screens, tumor-specific peptides, tumor-specific aptamers, Fab or scFv (i.e., a single chain variable region) fragments of antibodies such as, for example, an Fab fragment of an antibody directed to EphA2 or other proteins specifically expressed or uniquely accessible on metastatic cancer cells, growth factors, such as EGF, FGF, insulin, and insulin-like growth factors, and homologous polypeptides, somatostatin and its analogs, transferrin, lipoprotein complexes, Arg-Gly-Asp containing peptides, microtubule-associated sequence (MTAS), various galectins, δ-opioid receptor ligands, cholecystokinin A receptor ligands, ligands specific for angiotensin AT1 or AT2 receptors, peroxisome proliferator-activated receptor γ ligands, and other molecules that bind specifically to a receptor preferentially expressed on the surface of targeted cells or on an infectious organism, and fragments of any of these molecules. The term "a targeted receptor," as used herein, refers to a receptor expressed by a cell that can bind a cell targeting ligand. The receptor may be expressed on the surface of the cell. The receptor may be a transmembrane receptor. Examples of such targeted receptors include, but are not limited to, EGFR, αvβ3 integrin, somatostatin receptor, folate receptor, prostate-specific membrane antigen, CD105, mannose receptor, estrogen receptor, GM1 ganglioside, and the like. In some embodiments, cell penetrating peptides may also be attached to one or more PEG terminal groups in place of or in addition to the targeting ligand. As used herein, the terms “cell penetrating peptide” (“CPP”), “protein transduction domain” (“PTD”), or “membrane translocating sequence,” refer to short peptides (e.g., from 4 to about 40 amino acids) that have the ability to translocate across a cellular membrane to gain access to the interior of a cell and to carry into the cells a variety of covalently and noncovalently conjugated cargoes, including proteins, and oligonucleotides. In preferred embodiments, CPPs comprise: 1) a high relative abundance of positively charged amino acids (e.g., lysine or arginine); 2) an amino acid sequence that comprises an alternating pattern of polar, charged amino acids and non-polar, hydrophobic amino acids; or 3) an amino acid sequence that comprises hydrophobic peptides (e.g., mostly apolar residues with low net charge or Attorney Docket No.54926-0014WO1 hydrophobic amino acid groups). (See, e.g., US Pat. Pub. No.: 20220177494; Oliveira, E.C, et al., “Predicting cell-penetrating peptides using machine learning algorithms and navigating in their chemical space,” Scientific Reports., 11(1):7628 (2021); Derakhshankhah, H., and Jafari, S., “Cell penetrating peptides: A concise review with emphasis on biomedical applications,” Biomedicine & Pharmacotherapy., 108:1090- 1096 (2018); Milletti, F., “Cell-penetrating peptides: classes, origin, and current landscape,” Drug Discovery Today, 17(15–16):850-860 (2012); Stalmans, S., et al., “Chemical-functional diversity in cell-penetrating peptides,” PLOS ONE, 8(8):e71752 (2013); Wagstaff, K.M., and Jans, D.A., “Protein transduction: cell penetrating peptides and their therapeutic applications,” Current Medicinal Chemistry, 13(12):1371-1387 (2006), the entire contents of each of which are hereby incorporated by reference in their entirety). Examples of CPP peptides include, but are not limited to: TAT cell penetrating peptide; MAP; Penetratin or Antenapedia PTD; Penetratin-Arg; antitrypsin (358-374); Temporin L; Maurocalcine; pVEC (Cadherin- 5); Calcitonin; Neurturin; Penetratin; TAT-HA2 Fusion Peptide; TAT (47-57); SynB1; SynB3; PTD-4; PTD-5; FHV Coat-(35-49); BMV Gag-(7-25); HTLV-II Rex- (4-16); HIV-1 Tat (48-60) or D-Tat; R9-Tat; Transportan; SBP or Human P1; FBP; MPG(δNLS); Pep-1 or Pep-1-Cysteamine; Pep-2; Periodic sequences, Polyarginines (RxN (4<N<17) chimera); Polylysines (KxN (4<N<17) chimera); (RAca)6R; (RAbu)6R; (RG)6R; (RM)6R; (RT)6R; (RS)6R; R10; (RA)6R; and R7. As used herein, a “vector” means any nucleic acid or nucleic acid-bearing particle, cell, or organism capable of being used to transfer a nucleic acid into a host cell. The term “vector” includes both viral and nonviral products and means for introducing the nucleic acid into a cell. A “vector” can be used in vitro, ex vivo, or in vivo. Vectors capable of directing the expression of operatively linked genes are referred to herein as “expression vectors.” Non-viral vectors include plasmids, cosmids, artificial chromosomes (e.g., bacterial artificial chromosomes or yeast artificial chromosomes), liposomes, electrically charged lipids (cytofectins), DNA- protein complexes, and biopolymers, for example. Viral vectors include, but are not limited to, retroviruses, lentiviruses, adeno-associated virus, pox viruses, baculovirus, reoviruses, vaccinia viruses, herpes simplex viruses, Epstein-Barr viruses, and adenovirus vectors, for example. Vectors can also comprise the entire genome sequence or recombinant genome sequence of a virus. A vector can also comprise a portion of the genome that comprises the functional sequences to produce a virus Attorney Docket No.54926-0014WO1 capable of infecting, entering, or being introduced to a cell to deliver nucleic acid therein. The term “WW domain” as used herein, refers to a protein domain having two basic residues at the C-terminus that mediates protein-protein interactions with short proline-rich or proline-containing motifs. WW domains are further described herein. The term “Cas9,” or “Cas9 protein,” or “Cas9 polypeptide” refers to an RNA- guided nuclease comprising a Cas9 protein as well as fusion proteins containing such Cas9 proteins and variants thereof (e.g., a protein comprising an active, inactive, or altered DNA cleavage domain of Cas9, and / or the gRNA binding domain of Cas9). In some embodiments, the fused proteins may include those that modify the epigenome or control transcriptional activity. The variants may include deletions or additions, such as, e.g., addition of one, two, or more nuclear localization sequences (such as from SV40 and others known in the art), e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 such sequences or a range between and including any two of the foregoing values. In some embodiments, the Cas9 polypeptide is a Cas9 protein found in a type II CRISPR-associated system. Suitable Cas9 polypeptides that may be used in certain embodiments of the present invention include, but are not limited to, Cas9 protein from Streptococcus pyogenes (Sp. Cas9), F. novicida, S. aureus, S. thermophiles, N. meningitidis, and variants thereof. A Cas9 nuclease is also referred to sometimes as a casn1 nuclease or a CRISPR (clustered regularly interspaced short palindromic repeat)-associated nuclease. CRISPR is an adaptive immune system that provides protection against mobile genetic elements (e.g., viruses, transposable elements, and conjugative plasmids). CRISPR clusters contain spacers, sequences complementary to antecedent mobile elements, and target invading nucleic acids. CRISPR clusters are transcribed and processed into CRISPR RNA (crRNA). In type II CRISPR systems correct processing of pre-crRNA requires a trans-encoded small RNA (tracrRNA), endogenous ribonuclease 3 (mc) and a Cas9 protein. The tracrRNA serves as a guide for ribonuclease 3-aided processing of pre-crRNA. Subsequently, Cas9 / crRNA / tracrRNA endonucleolytically cleaves linear or circular dsDNA target complementary to the spacer. The target strand not complementary to crRNA is first cut endonucleolytically, then trimmed 3'-5' exonucleolytically. In nature, DNA- binding and cleavage typically requires protein and both RNAs. However, single guide RNAs (“sgRNA,”, or simply “gRNA”) can be engineered so as to incorporate Attorney Docket No.54926-0014WO1 aspects of both the crRNA and tracrRNA into a single RNA species. (See, e.g., Jinek M., et al., Science, 337:816-821 (2012), the entire contents of which is hereby incorporated by reference). Cas9 recognizes a short motif in the CRISPR repeat sequences (the PAM or protospacer adjacent motif) to help distinguish self versus non-self. Cas9 nuclease sequences and structures are well known to those of skill in the art. (See, e.g., Ferretti et al., “Complete genome sequence of an M1 strain of Streptococcus pyogenes,” Proc. Natl. Acad. Sci. U.S.A., 98:4658-4663 (2001); “CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III,” Deltcheva E., et al., “CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III,” Nature, 471:602-607 (2011); and Jinek, M., et al., “A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity,” Science, 337:816-821 (2012), the entire contents of each of which are incorporated herein by reference). Additional suitable Cas9 nucleases and sequences will be apparent to those of skill in the art based on this disclosure, and such Cas9 nucleases and sequences include Cas9 sequences from the organisms and loci disclosed in the art. (See, e.g., Chylinski, Rhun, and Charpentier, “The tracrRNA and Cas9 families of type II CRISPR-Cas immunity systems,” RNA Biology, 10:5, 726-737 (2013); Karvelis, G., et al., “Harnessing the natural diversity and in vitro evolution of Cas9 to expand the genome editing toolbox,” Current Opinion in Microbiology, 37:88-94 (2017); Komor, A. C., et al., “CRISPR-Based Technologies for the Manipulation of Eukaryotic Genomes,” Cell, 168:20-36 (2017); and Murovec, J., et al., “New variants of CRISPR RNA-guided genome editing enzymes,” Plant Biotechnol. J., 15:917-26 (2017), the entire contents of each of which are incorporated herein by reference). In some embodiments, the Cas9 polypeptide is a wild-type Cas9, a nickase, or comprises a nuclease inactivated (“dCas9” for nuclease-"dead" Cas9) protein. Methods for generating a Cas9 protein (or a variant thereof) having an inactive DNA cleavage domain are known (See, e.g., Jinek et al., Science.337:816-821(2012); Qi et al., “Repurposing CRISPR as an RNA-Guided Platform for Sequence-Specific Control of Gene Expression,” Cell, 28;152(5):1173-83 (2013), the entire contents of each of which are incorporated herein by reference). For example, the DNA cleavage domain of Cas9 is known to include two subdomains, the HNH nuclease subdomain and the RuvC1 subdomain. The HNH subdomain cleaves the strand complementary to the gRNA, whereas the RuvC1 subdomain cleaves the non-complementary strand. Attorney Docket No.54926-0014WO1 Mutations within these subdomains can silence the nuclease activity of Cas9. For example, the mutations D10A and H841A completely inactivate the nuclease activity of S. pyogenes Cas9 (Jinek et al., Science, 337:816-821 (2012); Qi et al., Cell, 28;152(5):1173-83 (2013)). In some embodiments, proteins comprising variants of Cas9 are provided. For example, in some embodiments, a protein comprises one of two Cas9 domains: (1) the gRNA binding domain of Cas9; or (2) the DNA cleavage domain of Cas9. In some embodiments, proteins comprising Cas9 or variants thereof are referred to as "Cas9 variants." A Cas9 variant shares homology to Cas9, or a variant thereof. For example, a Cas9 variant is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% to wild type Cas9. In some embodiments, the Cas9 variant comprises a variant of Cas9 (e.g., a gRNA binding domain or a DNA-cleavage domain), such that the variant is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% to the corresponding variant of wild type Cas9. In some embodiments, wild type Cas9 protein corresponds to the Cas9 protein from Streptococcus pyogenes (SEQ ID NO: 37; single underline: HNH domain; double underline: RuvC domain). In some embodiments, wild type Cas9 corresponds to, or comprisesSEQ IDNO: 38 (single underline: HNH domain; double underline: RuvC domain). In some embodiments, dCas9 corresponds to, or comprises in part or in whole, a Cas9 amino acid sequence having one or more mutations that inactivate the Cas9 nuclease activity. For example, in some embodiments, a dCas9 domain comprises mutation(s) at the amino acids corresponding to D10A and / or H820A of wild-type Cas9 (e.g., SEQ ID NO: 37). In other embodiments, dCas9 variants having mutations other than D10A and H820A are provided, which e.g., result in nuclease inactivated Cas9 (dCas9). Such mutations, by way of example, include other amino acid substitutions at D10 and H820, or other substitutions within the nuclease domains of Cas9 (e.g., substitutions in the HNH nuclease subdomain and / or the RuvC1 subdomain). In some embodiments, variants or homologues of dCas9 (e.g., a protein comprising or Attorney Docket No.54926-0014WO1 consisting of the polynucleic acid sequence of SEQ ID NO: 37 with mutations D10A and / or H820A) are provided which are at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% to dCas9. In some embodiments, variants of dCas9 are provided having amino acid sequences which are shorter, or longer than dCas9, by about 5 amino acids, by about 10 amino acids, by about 15 amino acids, by about 20 amino acids, by about 25 amino acids, by about 30 amino acids, by about 40 amino acids, by about 50 amino acids, by about 75 amino acids, by about 100 amino acids or more. In some embodiments, Cas9 fusion proteins as provided herein comprise the full-length amino acid of a Cas9 protein, e.g., one of the sequences provided above. In other embodiments, however, fusion proteins as provided herein do not comprise a full-length Cas9 sequence, but only a fragment thereof. For example, in some embodiments, a Cas9 fusion protein provided herein comprises a Cas9 fragment, wherein the fragment binds crRNA and tracrRNA or sgRNA, but does not comprise a functional nuclease domain, e.g., in that it comprises only a truncated version of a nuclease domain or no nuclease domain at all. Exemplary amino acid sequences of suitable Cas9 domains and Cas9 fragments are provided herein, and additional suitable sequences of Cas9 domains and fragments will be apparent to those of skill in the art. In some of these embodiments, the fusion protein comprises a transcriptional activator (e.g., VP64), a transcriptional repressor (e.g., KRAB, SID), a nuclease domain (e.g., FokI), base editors, prime editors, a recombinase domain (e.g., Hin, Gin, or Tn3), a deaminase (e.g., a cytidine deaminase or an adenosine deaminase) or an epigenetic modifier domain (e.g., TET1, p300). In some embodiments, Cas9 refers to Cas9 from: Corynebacterium ulcerans (NCBI Refs: NC_015683.1, NC_017317.1); Corynebacterium diphtheria (NCBI Refs: NC_016782.1, NC_016786.1); Spiroplasma syrphidicola (NCBI Ref: NC_021284.1); Prevotella intermedia (NCBI Ref: NC_017861.1); Spiroplasma taiwanense (NCBI Ref: NC_021846.1); Streptococcus iniae (NCBI Ref: NC_021314.1); Belliella baltica (NCBI Ref: NC_018010.1); Psychroflexus torquisl (NCBI Ref: NC_018721.1); Streptococcus thermophilus (NCBI Ref: YP_820832.1); Listeria innocua (NCBI Ref: NP 472073.1); Campylobacter jejuni (NCBI Ref: YP_002344900.1); or Neisseria meningitidis (NCBI Ref: YP_002342100.1). Attorney Docket No.54926-0014WO1 The term "deaminase" refers to an enzyme that catalyzes a deamination reaction. In some embodiments, the deaminase is a cytidine deaminase, catalyzing the hydrolytic deamination of cytidine or deoxycytidine to uracil or deoxyuracil, respectively. The terms "RNA-programmable nuclease" and "RNA-guided nuclease" are used interchangeably herein and refer to a nuclease that forms a complex with (e.g., binds or associates with) one or more RNA molecules that are not a target for cleavage. In some embodiments, an RNA-programmable nuclease, when in a complex with an RNA, may be referred to as a nuclease:RNA complex. RNA-programmable nucleases include Cas9 nucleases. Typically, the bound RNA(s) is referred to as a guide RNA (gRNA). gRNAs can exist as a complex of two or more RNAs, or as a single RNA molecule. gRNAs that exist as a single RNA molecule may be referred to as single-guide RNAs (sgRNAs), though "gRNA" is used interchangeably to refer to guide RNAs that exist as either single molecules or as two or more molecules. Typically, gRNAs that exist as single RNA species comprise two domains: (1) a domain that shares homology to a target nucleic acid (e.g., directs binding of a Cas9 complex to the target); and (2) a domain that binds a Cas9 protein. The gRNA comprises a nucleotide sequence that complements a target site, which mediates binding of the nuclease / RNA complex to said target site and provides the sequence specificity of the nuclease:RNA complex. The term "recombinase," as used herein, refers to a site-specific enzyme that mediates the recombination of DNA between recombinase recognition sequences, which results in the excision, integration, inversion, or exchange (e.g., translocation) of DNA fragments between the recombinase recognition sequences. Recombinases can be classified into two distinct families: serine recombinases (e.g., resolvases and invertases) and tyrosine recombinases (e.g., integrases). Examples of serine recombinases include, without limitation, Hin, Gin, Tn3, β-six, CinH, ParA, γδ, Bxb1, φC31, TP901, TG1, φBT1, R4, φRV1, φFC1, MR11, A118, U153, and gp29. Examples of tyrosine recombinases include, without limitation, Cre, FLP, R, Lambda, HK101, HK022, and pSAM2. The serine and tyrosine recombinase names stem from the conserved nucleophilic amino acid residue that the recombinase uses to attack the DNA and which becomes covalently linked to the DNA during strand exchange. Recombinases have numerous applications, including the creation of gene knockouts / knock-ins and gene therapy applications. (See, e.g., Brown et al., “Serine Attorney Docket No.54926-0014WO1 recombinases as tools for genome engineering,” Methods, 53(4):372-379 (2011); Hirano et al., “Site-specific recombinases as tools for heterologous gene integration,” Appl. Microbiol. Biotechnol., 92(2):227-239 (2011); Chavez and Calos, “Therapeutic applications of the ΦC31 integrase system,” Curr. Gene Ther., 11(5):375-381 (2011); Turan and Bode, “Site-specific recombinases: from tag-and-target- to tag-and- exchange-based genomic modifications,” FASEB J., 25(12):4088-4107 (2011); Venken and Bellen, “Genome-wide manipulations of Drosophila melanogaster with transposons, Flp recombinase, and ΦC31 integrase,” Methods Mol. Biol., 859:203- 228 (2012); Murphy, “Phage recombinases and their applications,” Adv. Virus Res., 83:367-414 (2012); Zhang et al., “Conditional gene manipulation: Cre-ating a new biological era,” J. Zhejiang Univ. Sci. B., 13(7):511-524 (2012); Karpenshif and Bernstein, “From yeast to mammals: recent advances in genetic control of homologous recombination,” DNA Repair (Amst), 1;11(10):781-788 (2012); the entire contents of each are hereby incorporated by reference in their entirety). The recombinases provided herein are not meant to be exclusive examples of recombinases that can be used in embodiments of the invention. The methods and compositions of the invention can be expanded by mining databases for new orthogonal recombinases or designing synthetic recombinases with defined DNA specificities. (See, e.g., Groth et al., “Phage integrases: biology and applications,” J. Mol. Biol., 335, 667-678 (2004); Gordley et al., “Synthesis of programmable integrases,” Proc. Natl. Acad. Sci. USA., 106, 5053-5058 (2009); the entire contents of each are hereby incorporated by reference in their entirety). Other examples of recombinases that are useful in the methods and compositions described herein are known to those of skill in the art, and any new recombinase that is discovered or generated is expected to be able to be used in the different embodiments of the invention. In some embodiments, a recombinase (or catalytic domain thereof) is fused to a Cas9 protein (e.g., dCas9). The terms “recombine” and “recombination,” in the context of a nucleic acid modification (e.g., a genomic modification), are used to refer to the process by which two or more nucleic acid molecules, or two or more regions of a single nucleic acid molecule, are modified by the action of a recombinase protein. Recombination can result in, inter alia, the insertion, inversion, excision, or translocation of a nucleic acid sequence, e.g., in or between one or more nucleic acid molecules. Attorney Docket No.54926-0014WO1 As used herein, the terms “approximately,” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (for example, when such number would exceed 100% of a possible value). DESCRIPTION OF DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. FIG.1 is a schematic of an example of ARMMs Cas9 / gRNA packaging and delivery to cells. FIG.2 is a set of bar graphs demonstrating high efficiency disruption of multiple genomic targets by ARMMs loaded with Cas9 / gRNA. FIG.3 depicts guide RNA screening for targeting the mouse Nlrp3 gene. The graph shows % indel of the Nlrp3 gene editing from the mouse neuro-2a cells with transient transfection of ARRDC1-Cas9 fusion protein and different gRNAs. FIG.4 shows the results of an in vitro experiment to demonstrate the dose dependent gene editing with ARMMs. FIG.5 shows the results of intranasal injection of ARMMs induced gene editing at NF-kB binding site in the mouse Nlrp3 gene. FIG.6 is a western blot and Jess data showing the Nlrp3 protein level after the ARMMs treatment in RAW264.7 cells and Bone marrow-derived macrophages (BMDM). FIG.7 depicts ELISA data showing the secreted IL-1b from the BMDM was decreased after ARMMs treatment. FIG.8 shows that intranasal injection of ARMMs induced gene editing at the exon region of the Nlrp3 gene in mouse. FIG.9 is a western blot showing the Irf-5 protein level after ARMMs treatment in RAW264.7 cells. Attorney Docket No.54926-0014WO1 FIG.10 depicts ELISA data showing that the secreted INF beta from the RAW264.7 cells was decreased after ARMMs treatment. FIG.11 shows that intranasal injection of ARMMs induced gene editing at the Irf-5 gene in mouse. FIG.12 demonstrates that Cre-payloaded ARMMs show strong functional delivery to alveolar macrophage in vitro. Cre-Payloaded ARMMs were added to primary alveolar macrophage isolated from Ai14 Cre-reporter mice at 1E4, 1E5, and 1E6 ARMMs per cell and incubated for 48-hrs. tdTomato expression was quantified by fluorescence microscopy (data displayed as graph on right). Representative images shows ARMMs added to primary cells at 1E6 ARMMs per cell. FIGS.13A–13E demonstrate that oral-tracheal treatment of Cre-payloaded ARMMs results in functional delivery to alveolar macrophages. FIG.13A: Schematic of dosing paradigm showing that female Cre-reporter mice (Ai9 / Ai14) were administered ARMMs oraltracheally and lungs harvested 96-hrs after administration. FIG.13B: Representative flow cytometry density plots of tdTomato signal in alveolar macrophages (defined as cd45+cd11chicd11bmidSiglecF+) in a PBS treated animal (left) or Cre-payloaded ARMMs treated animal (right). tdTomato positive alveolar macrophages are boxed inside the red gate. FIG.13C: Percentage of tdTomato positive alveolar macrophages out of total alveolar macrophages as determined by flow cytometry from n=6 mice administered Cre-payloaded ARMMs. FIG.13D: All five-lung lobes showed consistently tdTomato-positive alveolar macrophages FIG. 13E: Immunofluorescence of frozen lung cross sections from mice administered PBS (top row) or Cre-payloaded ARMMs (bottom row). Colocalization was determined by staining for Cd206 (macrophage marker) and visualizing native tdTomato fluorescence. FIGS.14A–14D demonstrate that oral-tracheal treatment of mCherry- payloaded ARMMs results in uptake in alveolar macrophages. FIG.14A: Schematic of dosing paradigm showing that female C57BL / 6 mice were administered ARMMs oraltracheally and lungs harvested 2-hrs after administration. FIG.14B: Representative flow cytometry density plots of mCherry uptake in alveolar macrophages (defined as cd45+cd11chicd11bmid) in a PBS-treated animal (left) or mCherry ARMMs-treated animal (right). mCherry positive alveolar macrophages are boxed inside the red gate. FIG.14C: Percentage of mCherry positive alveolar macrophages out of total alveolar macrophages as determined by flow cytometry from Attorney Docket No.54926-0014WO1 n=6 mice administered mCherry ARMMs. FIG.14D: Immunofluorescence of paraffin-embedded lung cross sections from mice administered PBS (top row) or mCherry-ARMMs (bottom row). Lung sections were stained for Cd206 (macrophage marker) and mCherry to visualize colocalization. FIGS.15A–15B demonstrate that stimulation of the NLRP3 inflammasome is suppressed after treatment with ARMMs targeting disruption of NLRP3. FIG.15A shows stimulation of NLRP3 inflammasome, as reflected by upregulation of NLRP3 protein levels, after treatment of alveolar macrophages with LPS and Nigericin. Alveolar macrophages were isolated from BAL of Mock or ARMMs treated mice. FIG.15B shows stimulation of NLRP3 inflammasome, as reflected by secretion of IL1β, after treatment of alveolar macrophages with LPS and Nigericin. Alveolar macrophages were isolated from BAL of Mock or ARMMs treated mice. FIG.16 shows a schematic of experimental plan used in Example 5, wherein test animals were treated with ARMMs payloaded with either Cas9 targeting NLRP3 3 days prior to CCl4 chemical insult to elicit inflammation. FIG.17A and FIG.17B demonstrate the levels of serum alanine transaminase (“ALT”) (FIG.17A) and serum aspartate transaminase (“AST”) (FIG.17B) assessed 24-hr after carbon tetrachloride (CCl4) administration in test animals. PBS vehicle control (n=7 mice), NLRP3 (n=7 mice) and MCC950 (n=7 mice). Statistical significance was determined through one-way ANOVA Dunnett test to PBS vehicle control. FIG.18 shows the deep sequencing of the NLRP3 locus in F4 / 80+ MACS purified cells from dissected livers of treated mice described in Example 5. FIG.19 shows a plot of the viability of isolated mouse liver non-parenchymal cells from dissected livers of treated mice untreated with CCl4(PBS control), and for cells harvested from mice that were treated with CCl4 to elicit liver injury and also administered either PBS, Cas9 payloaded ARMMs targeting NLRP3, or MCC950 (a small molecule MLPR3 inhibitor) as assessed in single cell suspensions in flow cytometry. FIG.20 shows the viability of cells within liver tissue sections of mice untreated with CCl4 (PBS control), and for cells harvested from mice that were treated with CCl4to elicit liver injury and also administered either PBS, Cas9 payloaded ARMMs targeting NLRP3 as assessed in terminal deoxynucleotidyl transferase dUTP nick end labeling (“TUNEL”) staining. Attorney Docket No.54926-0014WO1 FIG.21A shows the results of ARMMs.mCherry.P delivered intravenously to cynomolgus monkey and assessing mCherry native fluorescence among flow-gated cell populations from the liver of treated monkeys including CD45+ CD163+ Kupffer cells. FIG.21B shows a plot of flow-gated isolated Kupffer cells displaying mCherry signal from 5 collected liver sections after in vivo intravenous delivery of a single dose of 1x1013ARMMs.mCherry.P to cynomolgus monkeys. FIGS.22A-22C depict guide RNA screening for targeting the cynomolgus Nlrp3 gene. FIG.22A shows a plot of percent (%) indel formation in the NLPR3 gene in cynomolgus COS7 cells with transient transfection of ARRDC1-Cas9 fusion protein and different gRNAs comprising SEQ ID NOs 92-99, 17, 100, 101, 103, 105- 107, 110, and 112-114. FIG.22B shows a plot of percent (%) indel formation in the NLPR3 gene in COS7 cells at 1x106ARMMs / cell and 5x106ARMMs / cell for a subset of the gRNAs depicted in the plot of FIG.22A. FIG.22C shows a plot of percent (%) indel formation in the NLPR3 gene in purified cynomolgus monocytes at 1x106ARMMs / cell and 5x106ARMMs / cell for a subset of the gRNAs depicted in the plot of FIG.22A. FIG.23A shows a schematic of the study design for evaluating Cas9 payloaded ARMMs targeting cynomolgus NLRP3 in vivo using intravenous administration to cynomolgus monkeys. FIG.23B shows a plot of results of (percent) % indel formation in NLPR3 measured in isolated liver tissue of cynomolgus monkeys treated with Cas9 payloaded ARMMs targeting cynomolgus NLRP3. DETAILED DESCRIPTION Provided herein are compositions and methods for ARRDC1-mediated microvesicle-based modulation of inflammation and inflammatory disorders, e.g., by modulating the sequence and / or expression of an inflammatory gene target, e.g., as described herein. INFLAMMATORY TARGETS AND DISORDERS The compositions and methods described herein find use, for example, in the modulation of inflammation and inflammatory disorders by delivering therapeutic Attorney Docket No.54926-0014WO1 payloads that modulate inflammatory gene or protein targets (e.g., by one or more of: increasing expression levels of a target, decreasing expression levels of a target, delivering a functional copy of a target, or direct editing of a target). In some cases, the disorder is associated with mutation and / or dysregulation of a gene (or gene product thereof) selected from NLRP3 (e.g., NCBI Gene ID: 114548), IRF-5 (e.g., NCBI Gene ID: 3663), GSDMD (e.g., NCBI Gene ID: 79792), ASC (e.g., NCBI Gene ID: 29108), STING (e.g., NCBI Gene ID: 340061), IL-12 (e.g., NCBI Gene ID: 3592 and / or 3593), IL-10 (e.g., NCBI Gene ID: 3586, TNF-alpha (e.g., NCBI Gene ID: 7124), IL-6 (e.g., NCBI Gene ID: 24498), MCP-1 (e.g., NCBI Gene ID: 6347), IL-33 (e.g., NCBI Gene ID: 90865), TGF-beta (e.g., NCBI Gene ID: 7040), IL-27 (e.g., NCBI Gene ID: 246778), GM-CSF (e.g., NCBI Gene ID: 100137216), PU.1 (e.g., NCBI Gene ID: 6688), PPARgamma (e.g., NCBI Gene ID: 5468), NOS (e.g., NCBI Gene ID: 4842 and / or 4843), Lipoxin A4 (e.g., NCBI Gene ID: 2358), CD86 (e.g., NCBI Gene ID: 942), CD80 (e.g., NCBI Gene ID: 941), and portions, and combinations thereof. Examples of inflammatory targets and associated disorders are set forth below. NLRP3 (NACT, LRR and PYD domains-containing protein 3) NLRP3 is the sensor component of the NRP3 inflammasome. NLRP3 signaling leads to the generation of pro-inflammatory cytokines and to cell death through formation of a multiprotein complex known as the inflammasome. The wild-type human NLRP3 protein has six isoforms: the canonical isoform (UniProt Q96P20, SEQ ID NO: 83), and isoforms 1 (Q96P20-2), 3 (Q96P20-3), 4 (Q96P20-4), 5 (Q96P20-5), and 6 (Q96P20-6). NLRP3 is predominantly expressed in macrophages (PubMed:33231615, PubMed:34133077) including stellate macrophages, also known as, Kupffer–Browicz cells, and Kupffer cells (PubMed:27226092, PubMed:30635040) and alveolar macrophage (PubMed:23436933, PubMed:30152849). It is also expressed in dendritic cells, B- and T-cells (at protein level) (PubMed:11786556) (PubMed:17164409), in LPS- treated granulocytes, but not in resting cells (at protein level) (PubMed:17164409), in stratified non-keratinizing squamous epithelium, including oral, esophageal and ectocervical mucosa and in the Hassall's corpuscles in the thymus and, also, detected in the stratified epithelium covering the bladder and ureter (transitional mucosa) (at protein level) (PubMed:17164409); in lung epithelial cells (at protein level) Attorney Docket No.54926-0014WO1 (PubMed:23229815), in chondrocytes (PubMed:12032915), and at low levels in resting osteoblasts (PubMed:17907925). Expression in monocytes is very weak (at protein level) (PubMed:17164409). Inappropriate inflammasome activation has been associated with various diseases, such as familiar cold-associated autoinflammatory syndrome (FCAS1), Muckle-Wells syndrome (MWS), urate crystal-induced peritonitis, acute myocardial infarction, gout, psoriasis-like dermatitis, diabetic nephropathy, SLE, Stargardt disease type 1, Alzheimer's disease, atherosclerosis, atrial fibrillation, osteoarthritis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, cystic fibrosis, rheumatoid arthritis, ARDS, celiac disease , ASH, Silicosis, ischemia reperfusion, smoke / chemical injury, and metal overload syndromes. In some cases, mutations in NLRP3 and / or overexpression of NLRP3 lead to autoinflammatory diseases which lead to inflammation even in the absence of infection. Examples of diseases associated with NLRP3 are set forth below. Familial Cold Autoinflammatory Syndrome 1 (FCAS1) FCAS1 is a rare autosomal dominant systemic inflammatory disease characterized by recurrent episodes of maculopapular rash associated with arthralgias, myalgias, fever and chills, swelling of the extremities, and conjunctivitis after generalized exposure to cold. Rarely, some patients may also develop late-onset renal amyloidosis. Examples of mutations are associated with FCAS1, such as those shown in Table 1, below. Table 1. NLRP3 Variants Associated with FCAS1. VARIANT ID POSITION(S) RELATIVE CHANGE TO SE ID NO 83 MWS is a hereditary periodic fever syndrome characterized by fever, chronic recurrent urticaria, arthralgias, progressive sensorineural deafness, and reactive renal Attorney Docket No.54926-0014WO1 amyloidosis. The disease may be severe if generalized reactive amyloidosis occurs. Examples of mutations are associated with FCAS1, such as those shown in Table 2, below. Table 2. NLRP3 Variants Associated with MWS. VARIANT ID POSITION(S) RELATIVE CHANGE TO SEQ ID NO: 83 CINCA is a rare congenital inflammatory disorder characterized by a triad of neonatal onset of cutaneous symptoms, chronic meningitis, and joint manifestations with recurrent fever and inflammation. Examples of mutations are associated with CINCA, such as those shown in Table 3, below. Table 3. NLRP3 Variants Associated with CINCA. VARIANT ID POSITION(S) RELATIVE CHANGE TO SEQ ID NO: 83 Attorney Docket No.54926-0014WO1 Keratoendothelitis Fugax Hereditaria (KEFH) KEFH is an autosomal dominant corneal disease that periodically, and fleetingly, affects the corneal endothelium, stroma, and vision, eventually leading to central corneal stromal opacities in some patients. The disease is characterized by unilateral attacks of ocular pain, pericorneal injection, and photophobia. The acute symptoms vanish in 1-2 days but vision remains blurry for several weeks. The attacks start at the age of 3-12 years and can affect either eye. They generally decrease in frequency and get milder with age. Examples of mutations are associated with KEFH, such as those shown in Table 4, below. Table 4. NLRP3 Variants Associated with KEFH. VARIANT ID POSITION(S) RELATIVE CHANGE TO SEQ ID NO: 83 DFNA34 is a form of sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA34 is a postlingual, slowly progressive form with variable severity and variable additional features. Some DFNA34 patients have autoinflammatory manifestations. Examples of mutations are associated with CINCA, such as those shown in Table 5, below. Table 5. NLRP3 Variants Associated with DFNA34. VARIANT ID POSITION(S) RELATIVE CHANGE TO SE ID NO 83 GSDMD encodes the precursor of a pore-forming protein that plays a key role in host defense against pathogen infection and danger signals. Upon cleavage, the released N-terminal moiety (Gasdermin-D, N-terminal) binds to membranes and forms pores, triggering pyroptosis. GSDMD (e.g., Human GSDMD, UniProt P57764, SEQ ID NO: 84) is widely expressed, including in the suprabasal cells of esophagus, as well as in the isthmus / neck, pit, and gland of the stomach, suggesting preferential expression in differentiating cells. Attorney Docket No.54926-0014WO1 GSDMD has been associated with familiar cold-associated autoinflammatory syndrome, Muckle-Wells syndrome, urate cystal-induced peritonitis, acute myocardial infarction, gout, psoriasis-like dermatitis, diabetic nephrophathy, SLE, Stargardt disease type 1, Alzheimer's disease, atherosclerosis, atrial fibrillation, osteoarthritis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, cystic fibrosis, rhematoid arthritis, ARDS, celiac disease, ASH, Silicosis, ischemia reperfusion, smoke / chemical injury, and metal overload syndromes. IRF-5 (Interferon Regulatory Factor 5) IRF-5 encodes a member of the interferon regulatory factor (IRF) family, a group of transcription factors with diverse roles, including virus-mediated activation of interferon, and modulation of cell growth, differentiation, apoptosis, and immune system activity.. The wild-type human IRF-5 protein has six isoforms: the canonical isoform (UniProt Q13568, SEQ ID NO: 85), and isoforms 2 (Q13568-2), 3 (Q13568-3), 4 (Q13568-4), 5 (Q13568-5), and 6 (Q13568-6). IRF-5 is expressed in macrophage including Kupffer cells (PubMed:27942586) and alveolar macrophage (PubMed: 27759022), monocytes (PubMed:32444476), monocytes (PubMed:32444476), granulocytes, and over 100 other tissues. Inappropriate IRF-5 activation has been associated with various diseases, such as Sjogren's syndrome, rheumatoid arthritis, systemic lupus erythematosus (SLE), systemic scleroderma, multiple sclerosis, myositis, ulcerative colitis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, and ARDS. In some cases, mutations in IRF-5 and / or overexpression of IRF-5 lead to such diseases. Examples of diseases associated with IRF-5 are set forth below. Inflammatory Bowel Disease (IBD14) A chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology. It is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas Attorney Docket No.54926-0014WO1 are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints. An insertion-deletion polymorphism in IRF5 confers risk of inflammatory bowel diseases. See Dideberg et al., “An insertion-deletion polymorphism in the interferon regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases,” Hum. Mol. Genet.16:3008–16 (2007). Systemic Lupus Erythematosus 10 (SLEB10) SLE is a chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Polymorphism in IRF5 is associated with SLE. See Sigurdsson et al., “Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus eruthematosus,” Am. J. Hum. Genet.76:528–37 (2005). Rheumatoid Arthritis (RA) RA is an inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Variants of IRF5 are associated with RA. See Sigurdsson et al., “Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis,” Arthritis Rheum.56:2202–10 (2007). IL-6 (Interleukin-6) IL-6 is a cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism. IL-6 (e.g., Human IL-6, UniProt P05231, SEQ ID NO: 86) is widely expressed. IL-6 has been associated with rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, giant cell arteritis, Takayasu arteritis, Castleman disease, SLE, systemic sclerosis, cytokine release syndrome, uveitis, Attorney Docket No.54926-0014WO1 thyroid eye disease, erosive hand osteoarthritis, schizophrenia, Schnitzler syndrome, myocaridal infarction, familiar Mediterranean fever, COVID-19 penumonia. IL-12 (Interleukin-12) Interleukin-12 subunit alpha heterodimerizes with interleukin-12 subunit beta to form the IL-12 cytokine. IL-12 is primarily produced by professional antigen- presenting cells (APCs) such as B-cells and dendritic cells (DCs) as well as macrophages and granulocytes and regulates T-cell and natural killer-cell responses, induces the production of interferon-gamma (IFN-gamma), favors the differentiation of T-helper 1 (Th1) cells and is an important link between innate resistance and adaptive immunity. IL-12 (e.g., Human IL-12, UniProt P29459 and 29460, SEQ ID NO: 87 and SEQ ID NO: 88) is expressed in lymph node and 28 other tissues. IL-12 has been associated with Crohn's disease, ulcerative colitis, psoriasis, diabetes mellitus, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, lupus erythematosus, primary biliary cholangitis, Sjögren's syndrome. TNF alpha (Tumor Necrosis Factor) TNF (TNFa) is a cytokine that binds to TNFRSF1A / TNFR1 and TNFRSF1B / TNFBR. It is mainly secreted by macrophages. TNF (e.g., Human TNFA, UniProt P01375, SEQ ID NO: 89) is expressed in granulocytes and 89 other tissues. TNF has been associated with Rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis, psoriasis, noninfectious uveitis, and ankylosing spondylitis. GM-CSF (Granulocyte-macrophage colony-stimulating factor) GM-CSF (also known as colony-stimulating factor 2 [CSF2]) is a cytokine that controls the production, differentiation and function of granulocytes and macrophage. GM-CSF (Human CSF2, UniProt P04141, SEQ ID NO: 90) is elevated in ARDS (PubMed:35145069). Deficiencies of the GM-CSF pathway results in pulmonary alveolar proteinosis (PubMed:11826288). GM-CSF has been associated with pulmonary alveolar proteinosis, RA, osteoarthritis, MS, Crohn’s disease, ulcerative colitis, interstitial lung disease, aortic aneurysm, allergic asthma, obesity, COVID-19, psoriasis, axial spondyloarthritis, ankylosing spondylitis. Attorney Docket No.54926-0014WO1 PU.1 PU.1, encoded by the Spi1 gene, is a transcription factor with multiple roles in hematopoiesis including the regulation of genes in macrophage, granulocyte, dendritic cell and B cell lineages. PU.1 (human PU.1 UniProt P17947, SEQ ID NO: 91) is pivotal in the terminal differentiation of alveolar macrophage (PubMed: 12896880). PU.1 has been associated with pulmonary alveolar proteinosis, Grave’s disease, Hashimoto’s thyroiditis, MS, RA, psoriatic arthritis, psoriasis, systemic sclerosis, SLE, Sjogren’s syndrome, primary biliary cirrhosis, type 2 diabetes, Alzheimer’s disease, Parkinson’s disease, and allergic asthma. ARMMS The present invention provides methods, systems, and compositions for ARRDC1-mediated microvesicles (“ARMMs”) delivery of molecule(s) of interest (e.g., therapeutic agents), also referred to as payloads, to cells and tissues. Molecules of interest, whether naturally or non-naturally, occurring include, but are not limited to, proteins, nucleic acids, and small molecules that can preferably associate with one or more ARMM related proteins (e.g., ARRDC1), or can be modified to associate with more specifically, TSG101 or ARRDC1 or specific motif(s) therein. These associations facilitate the incorporation of the molecules into ARMMs, which in turn can be used to deliver the desired payload (molecule of interest) into a targeted cell. By way of example, but not limitation, a payload RNA can be fused to a trans-activation response (TAR) element, thereby allowing it to associate with an ARRDC1 protein that is fused to an RNA binding protein, such as a Tat protein (e.g., bovine TAT protein). Alternatively, a payload protein can be fused to one or more WW domains, which associate with the PPXY motif of ARRDC1. The association of the molecule to an ARMM-related protein (e.g., ARRDC1), facilitates the loading of the molecule into the ARRDC1-containing ARMM. Alternatively, the molecule can be fused to an ARMM protein (e.g., TSG101 or ARRDC1) to load the payload into the ARMM. The molecule can be fused to the ARMM protein (e.g., TSG101 or ARRDC1) via a linker that may be cleaved upon delivery to a target cell. The present invention further relates to compositions and methods of producing, testing, and administering ARMMs. More particularly, the present invention provides compositions and methods of producing, testing, and administering ARMMs comprising one or more therapeutic agents (e.g., biological Attorney Docket No.54926-0014WO1 molecules including, but not limited to, CRISPR / Cas9, and other similar endonucleases, base editors, small molecules, proteins, and nucleic acids (e.g., DNA, RNA, siRNA, mRNA, miRNA, and the like)). Also provided are methods of administering therapeutic agents associated with ARMMs, including, but not limited to, methods of treating or contacting cells and tissues in one or more exemplary dosing regimens (e.g., 1) in vivo administration of ARMMs to a patient; 2) ex vivo administration of ARMMs to target cells and implantation of the ARMMs treated cells to a / the patient; and 3) in vivo and ex vivo regimens). Additionally, the present invention relates to methods of manufacturing (e.g., culturing, clarifying, separating, and concentrating) the inventive compositions obtained from stable producer cell lines and / or from transient cell cultures. Arrestin Domain Containing Protein 1 mediated microvesicles (“ARMMs”) are extracellular vesicles (“EVs”) that are distinct from exosomes. The budding of ARMMs requires ARRDC1, which is localized to the cytosolic side of the plasma membrane and, through a tetrapeptide motif, recruits the ESCRT-I complex protein TSG101 to the cell surface to initiate the outward membrane budding. Thus, in contrast to exosomes, the biogenesis of ARMMs occurs at the plasma membrane. ARMMs exhibit several additional features that make them potentially ideal vehicles for therapeutic delivery. ARRDC1 is not only necessary but also sufficient to drive ARMMs budding. Overexpression of the ARRDC1 protein increases the production of ARMMs in cells. This allows controlled production of ARMMs using modern biological manufacturing methods. Moreover, endogenous proteins such as cell surface receptors are actively recruited into ARMMs and can be delivered into recipient cells to initiate intercellular communication, suggesting that the exogenous payload molecules may be similarly packaged and delivered via ARMMs. In some cases, the ARMM further comprises a targeting moiety, e.g., that targets particular cell type(s), e.g., as described herein. ARRDC1 In preferred embodiments, ARRDC1 is a protein that comprises a PSAP (SEQID NO: 35) motif and a PPXY motif in its C-terminus, and interacts with TSG101 as shown herein. It should be appreciated that the PSAP (SEQ ID NO: 35) motif and the PPXY motif are not required to be at the absolute C-terminal end of the ARRDC1. Rather, they may be at a C-terminal portion of the ARRDC1 protein (e.g., the C- Attorney Docket No.54926-0014WO1 terminal half of the ARRDC1). The disclosure also contemplates variants of ARRDC1, such as fragments of ARRDC1 and / or ARRDC1 proteins that have a degree of identity (e.g., 60%, 70%, 80%, 85%, 90%, 95%, 98%, or 99% identity) to an ARRDC1 protein and are capable if interacting with TSG101. Accordingly, an ARRDC1 protein may be a protein that comprises a PSAP (SEQ ID NO: 35) motif and a PPXY motif and interacts with TSG101. In some embodiments, the ARRDC1 protein is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 39, SEQ ID NO: 40, or SEQ ID NO: 41, comprises a PSAP (SEQ ID NO: 35) motif and a PPXY motif, and interacts with TSG101. In some embodiments, the ARRDC1 protein has at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 110, at least 120, at least 130, at least 140, at least 150, at least 160, at least 170, at least 180, at least 190, at least 200, at least 210, at least 220, at least 230, at least 240, at least 250, at least 260, at least 270, at least 280, at least 290, at least 300, at least 310, at least 320, at least 330, at least 340, at least 350, at least 360, at least 370, at least 380, at least 390, at least 400, at least 410, at least 420, or at least 430 identical contiguous amino acids of any one of SEQ ID NO: 39, SEQ ID NO: 40, or SEQ ID NO: 41, comprises a PSAP (SEQ ID NO: 35) motif and a PPXY motif, and interacts with TSG101. In some embodiments, the ARRDC1 protein has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more mutations compared to any one of the amino acid sequences set forth in SEQ ID NO: 39, SEQ ID NO: 40, or SEQ ID NO: 41, comprises a PSAP (SEQ ID NO: 35) motif and a PPXY motif, and interacts with TSG101. In some embodiments, the ARRDC1 protein comprises any one of the amino acid sequences set forth in SEQ ID NO: 39, SEQ ID NO: 40, or SEQ ID NO: 41. Exemplary, non-limiting ARRDC1 protein sequences are provided herein, and additional, suitable ARRDC1 protein variants according to aspects of this invention are known in the art. It will be appreciated by those of skill in the art that this invention is not limited in this respect. Exemplary ARRDC1 sequences include SEQ ID NO: 39, SEQ ID NO: 40, and SEQ ID NO: 41 (PSAP and PPXY motifs are marked). Attorney Docket No.54926-0014WO1 TSG101 In certain embodiments, the inventive microvesicles further comprise TSG101 (tumor susceptibility gene 101) TSG101 belongs to a group of putative inactive homologs of ubiquitin-conjugating enzymes. The protein contains a coiled-coil domain that interacts with stathmin, a cytosolic phosphoprotein implicated in tumorigenesis. TSG101 is a protein that comprises a UEV domain and interacts with ARRDC1. As referred to herein, UEV refers to the Ubiquitin E2 variant domain of approximately 145 amino acids. The structure of the domain contains a α / β fold similar to the canonical E2 enzyme but has an additional N-terminal helix and further lacks the two C-terminal helices. Often found in TSG101 / Vps23 proteins, the UEV interacts with a ubiquitin molecule and is essential for the trafficking of a number of ubiquitylated payloads to multivesicular bodies (MVBs). Furthermore, the UEV domain can bind to Pro-Thr / Ser-Ala-Pro peptide ligands, a fact exploited by viruses such as HIV. Thus, the TSG101 UEV domain binds to the PTAP tetrapeptide motif in the viral Gag protein that is involved in viral budding. The disclosure also contemplates variants of TSG101, such as fragments of TSG101 and / or TSG101 proteins that have a degree of identity (e.g., 60%, 70%, 80%, 85%, 90%, 95%, 98%, or 99% identity) to a TSG101 protein and are capable of interacting with ARRDC1. Accordingly, a TSG101 protein may be a protein that comprises a UEV domain and interacts with ARRDC1. In some embodiments, the TSG101 protein is at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44, comprises a UEV domain, and interacts with ARRDC1. In some embodiments, the TSG101 protein has at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 110, at least 120, at least 130, at least 140, at least 150, at least 160, at least 170, at least 180, at least 190, at least 200, at least 210, at least 220, at least 230, at least 240, at least 250, at least 260, at least 270, at least 280, at least 290, at least 300, at least 310, at least 320, at least 330, at least 340, at least 350, at least 360, at least 370, at least 380, or at least 390, and any integer between the numbers, identical contiguous amino acids of any one of SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44, comprises a UEV domain and interacts with ARRDC1. In some embodiments, the TSG101 protein has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, Attorney Docket No.54926-0014WO1 50 or more mutations compared to any one of the amino acid sequences set forth in SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44 and comprises a UEV domain. In some embodiments, the ARRDC1 protein comprises any one of the amino acid sequences set forth in SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44. Exemplary, non-limiting TSG101 protein sequences are provided herein, and additional, suitable TSG101 protein sequences, isoforms, and variants are known in the art. It will be appreciated by those of skill in the art that this invention is not limited in this respect. Exemplary TSG101 sequences include SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44 (the UEV domain in these sequences includes amino acids 1-145 and is underlined in the sequences). The structure of UEV domains is known to those of skill in the art. (See, e.g., Owen Pornillos et al., Structure and functional interactions of the Tsg101 UEV domain, EMBO J., 21(10): 2397–2406 (2002), the entire contents of which are incorporated herein by reference). WW Domains WW domains are protein domains having two basic residues at the C-terminus that mediates protein-protein interactions with short proline-rich or proline-containing motifs. It should be appreciated that the two basic residues (e.g., any two of: H, R, and K) of the WW domain are not required to be at the absolute C-terminal end of the WW protein domain. Rather, the two basic residues may be at a C-terminal portion of the WW protein domain (e.g., the C-terminal half of the WW protein domain). In some embodiments, the WW domain contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 tryptophan (W) residues. In some embodiments, the WW domain contains at least two W residues. In some embodiments, the at least two W residues are spaced apart by from 15-25 amino acids. In some embodiments, the at least two W residues are spaced apart by from 19-23 amino acids. In some embodiments, the at least two W residues are spaced apart by from 20-22 amino acids. The WW domain possessing the two basic C-terminal amino acid residues may have the ability to associate with short proline-rich or proline-containing motifs (e.g., a PPXY motif). WW domains bind a variety of distinct peptide ligands including motifs with core proline-rich sequences, such as PPXY, which is found in ARRDC1. A WW domain may be a 30-40 amino acid protein interaction domain with two signature tryptophan residues spaced by 20- 22 amino acids. The three-dimensional structure of WW domains shows that they Attorney Docket No.54926-0014WO1 generally fold into a three-stranded, antiparallel β sheet with two ligand-binding grooves. WW domains are found in many eukaryotes and are present in approximately 50 human proteins (Bork, P. & Sudol, M., “The WW domain: a signaling site in dystrophin?” Trends Biochem Sci., 19, 531-533 (1994)). WW domains may be present together with several other interaction domains, including membrane targeting domains, such as C2 in the NEDD4 family proteins, the phosphotyrosine-binding (PTB) domain in FE65 protein, FF domains in CA150 and FBPIl, and pleckstrin homology (PH) domains in PLEKHA5. WW domains are also linked to a variety of catalytic domains, including HECT E3 protein-ubiquitin ligase domains in NEDD4 family proteins, rotomerase or peptidyl prolyisomerase domains in Pinl, and Rho GAP domains in ArhGAP9 and ArhGAP12. The WW domain may be a WW domain that naturally possesses two basic amino acids at the C-terminus. In some embodiments, a WW domain or WW domain variant may be from the human ubiquitin ligase WWP1, WWP2, Nedd4-1, Nedd4-2, Smurf1, Smurf2, ITCH, NEDL1, or NEDL2. Exemplary amino acid sequences of WW domain containing proteins (and their WW domains) are set forth in SEQ ID NO: 45–SEQ ID NO: 82. It should be appreciated that any of the WW domains or WW domain variants of the exemplary proteins may be used in the invention, described herein, and are not meant to be limiting. In some embodiments, the WW domain consists essentially of a WW domain or WW domain variant. Consists essentially of means that a domain, peptide, or polypeptide consists essentially of an amino acid sequence when such an amino acid sequence is present with only a few additional amino acid residues, for example, from about 1 to about 10 or so additional residues, typically from 1 to about 5 additional residues in the domain, peptide, or polypeptide. Alternatively, the WW domain may be a WW domain that has been modified to include two basic amino acids at the C-terminus of the domain. Techniques are known in the art and are described in the art, for example, in Sambrook et al., Molecular Cloning: a Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press (2001). Thus, a skilled person could readily modify an existing WW domain that does not normally have two C-terminal basic residues so as to include two basic residues at the C-terminus. Attorney Docket No.54926-0014WO1 Basic amino acids are amino acids that possess a side-chain functional group that has a pKa of greater than 7 and includes lysine, arginine, and histidine, as well as basic amino acids that are not included in the twenty α-amino acids commonly included in proteins. The two basic amino acids at the C-terminus of the WW domain may be the same basic amino acid or may be different basic amino acids. In one embodiment, the two basic amino acids are two arginines. The term WW domain also includes variants of a WW domain provided that any such variant possesses two basic amino acids at its C-terminus and maintains the ability of the WW domain to associate with the PPXY motif. A variant of such a WW domain refers to a WW domain that retains the ability of the variant to associate with the PPXY motif (i.e., the PPXY motif of ARRDC1 and that has been mutated at one or more amino acids, including point, insertion, and / or deletion mutations, but still retains the ability to associate with the PPXY motif. A variant or derivative, therefore, includes deletions, including truncations and fragments; insertions and additions, for example, conservative substitutions, site-directed mutants and allelic variants; and modifications, including one or more non-amino acyl groups (e.g., sugar, lipid, etc.) covalently linked to the peptide and post-translational modifications. In making such changes, substitutions of like amino acid residues can be made on the basis of relative similarity of side-chain substituents, for example, their size, charge, hydrophobicity, hydrophilicity, and the like, and such substitutions may be assayed for their effect on the function of the peptide by routine testing. The WW domain may be part of a longer protein. Thus, the protein, in various different embodiments, comprises the WW domain, consists of the WW domain, or consists essentially of the WW domain, as defined herein. The polypeptide may be a protein that includes a WW domain as a functional domain within the protein sequence. Expression Constructs Some aspects of this invention provide expression constructs for encoding a gene product or gene products that induce or facilitate the generation of ARMMs in cells harboring such a construct. In some embodiments, the expression constructs described herein encode a fusion protein as described herein, such as ARRDC1 fusion proteins and TSG101 fusion proteins. In some embodiments, the expression constructs encode an ARRDC1 protein, or variant thereof, and / or a TSG101 protein, Attorney Docket No.54926-0014WO1 or variant thereof. In some embodiments, overexpression of either or both gene products in a cell increases the production of ARMMs in the cell, thus turning the cell into a microvesicle producing cell. In some embodiments, such an expression construct comprises at least one restriction or recombination site that allows in-frame cloning of a protein sequence to be fused, either at the C-terminus, or at the N- terminus of the encoded ARRDC1, or variant thereof. As another example, an expression construct comprises at least one restriction or recombination site that allows in-frame cloning of a protein sequence to be fused either at the C-terminus or at the N-terminus of one or more encoded WW domains. In some embodiments, the expression construct comprises (a) a nucleotide sequence encoding an ARRDC1 protein, or variant thereof, operably linked to a heterologous promoter, and (b) a restriction site or a recombination site positioned adjacent to the ARRDC1-encoding nucleotide sequence allowing for the insertion of a nucleotide sequencing encoding a payload protein, or an RNA binding protein or RNA binding protein variant sequence, in frame with the ARRDC1-encoding nucleotide sequence. In some embodiments, the heterologous promoter may be a constitutive promoter, in some embodiments, the heterologous promoter may be an inducible promoter. Some aspects of this invention provide an expression construct comprising (a) a nucleotide sequence encoding a TSG101 protein, or variant thereof, operably linked to a heterologous promoter, and (b) a restriction site or a recombination site positioned adjacent to the TSG101-encoding nucleotide sequence allowing for the insertion of a nucleotide sequencing encoding a payload protein, or an RNA binding protein, DNA binding protein, or variant sequence thereof, in frame with the TSG101-encoding nucleotide sequence. In some embodiments, the heterologous promoter may be a constitutive promoter, in some embodiments, the heterologous promoter may be an inducible promoter. Some aspects of this invention provide an expression construct comprising (a) a nucleotide sequence encoding a WW domain, or variant thereof, operably linked to a heterologous promoter, and (b) a restriction site or a recombination site positioned adjacent to the WW domain-encoding nucleotide sequence allowing for the insertion of a payload protein or RNA binding protein, or a protein variant sequence thereof in frame with the WW domain-encoding nucleotide sequence. In some embodiments, the heterologous promoter may be a constitutive promoter, in some embodiments, the heterologous promoter may be an inducible promoter. The expression constructs may Attorney Docket No.54926-0014WO1 encode a payload protein, or an RNA binding protein fused to at least one WW domain. In some embodiments, the expression constructs encode a payload protein or an RNA binding protein, or variant thereof, fused to at least one WW domain, or variant thereof. Any of the expression constructs, described herein, may encode any WW domain or variant thereof. In some embodiments, the heterologous promoter may be a constitutive promoter, in some embodiments, the heterologous promoter may be an inducible promoter. The expression constructs, described herein, may comprise any nucleic acid sequence capable of encoding a WW domain or variant thereof. For example, a nucleic acid sequence encoding a WW domain or WW domain variant may be from the human ubiquitin ligase WWP1, WWP2, Nedd4-1, Nedd4-2, Smurf1, Smurf2, ITCH, NEDL1, or NEDL2. Some aspects of this invention provide expression constructs that encode any of the proteins, nucleic acids, such as RNAs, or fusions thereof described herein. Nucleic acids encoding any of the proteins and / or nucleic acid (including RNA) described herein, may be in any number of nucleic acid vectors known in the art. Vectors suitable for use in the compositions and methods of the present invention include both viral and nonviral products and additional means for introducing nucleic acid(s) into cells. Expression of any of the proteins and / or nucleic acid (including RNA) described herein, may be controlled by any regulatory sequence (e.g., a promoter sequence) known in the art. Regulatory sequences, as described herein, are nucleic acid sequences that regulate the expression of a nucleic acid sequence. A regulatory or control sequence may include sequences that are responsible for expressing a particular nucleic acid or may include other sequences, such as heterologous, synthetic, or partially synthetic sequences. The sequences can be of eukaryotic, prokaryotic, or viral origin that stimulate or repress transcription of a gene in a specific or non-specific manner and in an inducible or non-inducible manner. Regulatory or control regions may include origins of replication, RNA splice sites, introns, chimeric or hybrid introns, promoters, enhancers, transcriptional termination sequences, poly A sites, locus control regions, signal sequences that direct the polypeptide into the secretory pathways of the target cell. A heterologous regulatory region is a regulatory region not naturally associated with the expressed nucleic acid it is linked to. Included among the heterologous regulatory regions are regulatory Attorney Docket No.54926-0014WO1 regions from a different species, regulatory regions from a different gene, hybrid regulatory sequences, and regulatory sequences that do not occur in nature, but which are designed by one of ordinary skill in the art. Exemplary Cells Producing ARMMs Containing Payload A microvesicle-producing cell of the present invention may be a cell containing any of the expression constructs, any of the fusion proteins, or any of the payloads of molecules (e.g., biological molecules, small molecules, proteins, and nucleic acids described herein. For example, an inventive microvesicle-producing cell may contain one or more recombinant expression constructs encoding (1) an ARRDC1 protein, or PSAP (SEQ ID NO: 35) motif-containing variant thereof and (2) an RNA binding protein (e.g., a Tat protein), that is associated with the ARRDC1 protein, or PSAP (SEQ ID NO: 35) motif-containing variant thereof. In some embodiments, a microvesicle-producing cell may contain one or more recombinant expression constructs encoding (1) an ARRDC1 protein, or PSAP (SEQ ID NO: 35) motif-containing variant thereof, and (2) a payload protein, such as an RNA binding protein fused to at least one WW domain, or variant thereof, under the control of a heterologous promoter. In certain embodiments, the expression construct in the microvesicle producing cell encodes a payload protein with one or more WW domains or variants thereof. In certain embodiments, an expression construct in the microvesicle producing cell encodes an RNA that associates with (e.g., binds specifically) an RNA binding protein, for example a therapeutic RNA. Any of the expression constructs, described herein, may be stably inserted into the genome of the cell. In some embodiments, the expression construct is maintained in the cell, but not inserted into the genome of the cell. In some embodiments, the expression construct is in a vector, for example, a plasmid vector, a cosmid vector, a viral vector, or an artificial chromosome. In some embodiments, the expression construct further comprises additional sequences or elements that facilitate the maintenance and / or the replication of the expression construct in the microvesicle- producing cell, or that improve the expression of the fusion protein in the cell. Such additional sequences or elements may include, for example, an origin of replication, an antibiotic resistance cassette, a polyA sequence, and / or a transcriptional isolator. Some expression constructs suitable for the generation of microvesicle producing cells according to aspects of this invention are described elsewhere herein. Methods Attorney Docket No.54926-0014WO1 and reagents for the generation of additional expression constructs suitable for the generation of microvesicle producing cells according to aspects of this invention will be apparent to those of skill in the art based on the present disclosure. In some embodiments, the microvesicle producing cell is a mammalian cell, for example, a mouse cell, a rat cell, a hamster cell, a rodent cell, or a nonhuman primate cell. In some embodiments, the microvesicle producing cell is a human cell. One skilled in the art may employ conventional techniques, such as molecular or cell biology, virology, microbiology, and recombinant DNA techniques. Exemplary techniques are explained fully in the literature. For example, one may rely on the following general texts to make and use the invention: Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, and Sambrook et al., Third Edition (2001); DNA Cloning: A Practical Approach, Volumes I and II (D.N. Glover ed.1985); Oligonucleotide Synthesis (M.J. Gaited.1984); Nucleic Acid Hybridization (B.D. Hames & S.J. Higgins eds. (1985)); Transcription and Translation Hames & Higgins, eds. (1984); Animal Cell Culture (RI. Freshney, ed. (1986)); Immobilized Cells And Enzymes (IRL Press, (1986)); Gennaro et al., (eds.) Remington's Pharmaceutical Sciences, 18th edition; B. Perbal, A Practical Guide To Molecular Cloning (1984); F.M. Ausubel et al., (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (updates through 2001), Coligan et al., (eds.), Current Protocols in Immunology, John Wiley & Sons, Inc.(updates through 2001); W. Paul et al., (eds.) Fundamental Immunology, Raven Press; E.J. Murray et al., (ed.) Methods in Molecular Biology: Gene Transfer and Expression Protocols, The Humana Press Inc. (1991)(especially vol.7); and J.E. Celis et al., Cell Biology: A Laboratory Handbook, Academic Press (1994). Delivery of ARMMs Containing Payload Molecules ARMMs containing any of the expression constructs and / or any of the payload of molecules (e.g., therapeutic agents, biological molecules, small molecules, proteins, and nucleic acids (e.g., DNA, RNA), DNA plasmids, siRNA, shRNA, mRNA)) described herein, may optionally further comprise a targeting moiety. The targeting moiety may be used to target the delivery of ARMMs to specific cell types, resulting in the release of the contents of the ARMM into the cytoplasm of the Attorney Docket No.54926-0014WO1 specific targeted cell type. A targeting moiety may be a viral envelope protein, or portion thereof, that normally functions to aid viral attachment and entry into cells. A targeting moiety may selectively bind a surface antigen of the target cell. For example, the targeting moiety may be a membrane-bound immunoglobulin, an integrin, a receptor, a receptor ligand, an aptamer, a small molecule, or a variant thereof. Any number of cell surface proteins may also be included in an ARMM to facilitate the binding of an ARMM to a target cell and / or to facilitate the uptake of an ARMM into a target cell. Additional molecules, such as synthetic small molecules or natural products, can be modified to associate with an ARMM protein (e.g., TSG101 or ARRDC1) for the purpose of targeting. This association can facilitate their incorporation with ARMMs, which in turn can be used to augment delivery of ARMMs to target cells. The incorporation of a cleavable linker may be used to allow the small molecule to be released upon delivery in or to a target cell. As a non-limiting example, a small molecule can be linked to biotin, thereby allowing it to associate with an ARRDC1 protein which is fused to a streptavidin. As another non-limiting example, a small molecule can be linked to synthetic high affinity ligand that specifically binds to a mutant form of FKBP12 such as FKBP12(F36V) (Yang, W., et al., “Investigating protein-ligand interactions with a mutant FKBP possessing a designed specificity pocket” J. Med. Chem., 43(6):1135-1142 (2000)), which will associate with an ARRDC1 protein which is fused to FKBP12(F36V). The association of the small molecule to an ARMM protein (e.g., TSG101 or ARRDC1), facilitates the loading of the small molecule into the ARRDC1-containing ARMM. Some aspects of this invention relate to the recognition that ARMMs are taken up by target cells and ARMM uptake results in the release of the contents of the ARMM into the cytoplasm of the target cells. In some embodiments, the payload is an agent that affects a desired change in the target cell, for example, a change in cell survival, proliferation rate, a change in differentiation stage, a change in cell identity, a change in chromatin state, a change in the transcription rate of one or more genes, a change in the transcriptional profile, or a post-transcriptional change in gene compression of the target cell, and the like. It will be understood by those of skill in the art, that the agent to be delivered will be chosen according to the desired effect in the target cell. Attorney Docket No.54926-0014WO1 In some embodiments, cells from a subject are obtained and a payload is delivered to the cells by a system or method provided herein ex vivo. In some embodiments, the treated cells are selected for those cells in which a desired gene is expressed or repressed. In some embodiments, treated cells carrying a desired payload are returned to the subject they were obtained from. In some embodiments, the ARMMs further comprise a detectable label. In certain embodiments, detectably labeled ARMMs allow for the labeling of target cells without genetic manipulation. Detectable labels suitable for direct delivery to target cells are known in the art, and include, but are not limited to, fluorescent proteins, fluorescent dyes, membrane-bound dyes, and enzymes, for example, membrane- bound or cytosolic enzymes, catalyzing the reaction resulting in a detectable reaction product. Detectable labels suitable according to some aspects of this invention further include membrane-bound antigens, for example, membrane-bound ligands that can be detected with commonly available antibodies or antigen binding agents. Detectably labeled ARRMs find use in various diagnostic and analytical methods and applications. In some embodiments, ARMMs are provided that comprise a payload RNA that encodes a transcription factor, a transcriptional repressor, a fluorescent protein, a kinase, a phosphatase, a protease, a ligase, a chromatin modulator, a recombinase, and the like. In some embodiments, ARMMs are provided that comprise a payload RNA that inhibits the expression of a transcription factor, a transcriptional repressor, a fluorescent protein, a kinase, a phosphatase, a protease, a ligase, a chromatin modulator, or a recombinase. In some embodiments, the payload RNA is a therapeutic RNA. In some embodiments, the payload RNA is an RNA that affects a change in the state or identity of a target cell. For example, in some embodiments, the payload RNA encodes a reprogramming factor. Suitable transcription factors, transcriptional repressors, fluorescent proteins, kinases, phosphatases, proteases, ligases, chromatin modulators, recombinases, and reprogramming factors may be encoded by a payload RNA that is associated with a binding RNA to facilitate their incorporation into ARMMs and their function may be tested by any methods that are known to those skilled in the art, and the invention is not limited in this respect. Methods for isolating the ARMMs described herein are also provided. One exemplary method includes employing conventional techniques of collecting culture medium, or supernatant, from a cell culture comprising microvesicle-producing cells. Attorney Docket No.54926-0014WO1 In some embodiments, the cell culture comprises cells obtained from a subject, for example, cells suspected to exhibit a pathological phenotype, for example, a hyperproliferative phenotype. In some embodiments, the cell culture comprises genetically engineered cells producing ARMMs, for example, cells expressing a recombinant protein, for example, a recombinant ARRDC1 or TSG101 protein, such as an ARRDC1 or TSG101 protein, optionally fused to an RNA binding protein (e.g., a Tat protein) or variant thereof. In some embodiments, the supernatant is pre-cleared of cellular debris by centrifugation, for example, by two consecutive centrifugations of increasing G value (e.g., 500G and 2000G). In some embodiments, the method comprises passing the supernatant through a 0.2 µm filter, eliminating all large pieces of cell debris and whole cells. In some embodiments, the supernatant is subjected to ultracentrifugation, for example, at 120,000G for 2 hours, depending on the volume of centrifugate. The pellet obtained comprises microvesicles. In some embodiments, exosomes are depleted from the microvesicle pellet by staining and / or sorting (e.g., by FACS or MACS) using an exosome marker as described herein. Isolated or enriched ARMMs can be suspended in culture media or a suitable buffer, as described herein. Methods of ARMMs-Mediated Delivery of Payload to Cells Some aspects of this invention provide a method of delivering an agent (e.g., a therapeutic agent or agents) to a target cell. The target cell can be contacted with an ARMM in different ways. For example, a target cell may be contacted directly with an ARMM as described herein, or with an isolated ARMM from a microvesicle producing cell. The contacting can be done in vitro by administering the ARMM to the target cell in a culture dish, or in vivo by administering the ARMM to a subject. In some embodiments, the ARMMs are produced from cells obtained from a subject. In some embodiments, ARMMs that are produced from a cell obtained from a particular subject are administered to the same subject. Conversely, in some other embodiments, ARMMs produced from a cell that was obtained from the subject are administered to a different subject. As one example, a cell may be obtained from a subject and engineered to express one or more of the constructs provided herein (e.g., engineered to express a payload RNA associated with a binding RNA, an ARRDC1 protein, an ARRDC1 protein fused to an RNA binding protein, an RNA binding protein fused to a WW domain, a Cas9 protein, guide and regulator sequences, and the like). Attorney Docket No.54926-0014WO1 Alternatively, a target cell can be contacted with a microvesicle producing cell as described herein, for example, contacted in vitro by co-culturing the target cell and the microvesicle producing cell, or contacted in vivo by administering a microvesicle producing cell to a subject harboring the target cell. Accordingly, the method may include contacting the target cell with a microvesicle, for example, an ARMM containing any of the payloads to be delivered, as described herein. The target cell may be contacted with a microvesicle-producing cell, as described herein, or with an isolated microvesicle that has a lipid bilayer, an ARRDC1 protein or variant thereof, a payload (e.g., therapeutic agent(s)). It should be appreciated that the target cell may be of any origin, for example, from an organism. In some embodiments, the target cell is a mammalian cell. Some non-limiting examples of a mammalian cell include, without limitation, a mouse cell, a rat cell, a hamster cell, a rodent cell, and a nonhuman primate cell. In some embodiments, the target cell is a human cell. It should also be appreciated that the target cell may be of any cell type. In other cases, the target cell may be any differentiated cell type found in a subject. In some embodiments, the target cell is a cell in vitro, and the method includes administering the microvesicle to the cell in vitro, or co-culturing the target cell with the microvesicle-producing cell in vitro. In some embodiments, the target cell is a cell in a subject, and the method comprises administering the microvesicle or the microvesicle-producing cell to the subject. In some embodiments, the subject is a mammalian subject, for example, a rodent, a mouse, a rat, a hamster, or a non-human primate. In some embodiments, the subject is a human subject. In some embodiments, the target cell is a pathological cell. In some embodiments, the target cell is a phagocyte (e.g., a macrophage, e.g., as described herein). In some embodiments, the microvesicle is associated with a binding agent that selectively binds an antigen on the surface of the target cell. In some embodiments, the compositions and methods of the present invention comprise one or more targeting ligands that associate (e.g., bind) to one or more targeting receptors. In some embodiments, the antigen of the target cell is a cell surface antigen. The choice of the binding agent will depend, of course, on the identity or the type of target cell. It will be appreciated that the present invention is not limited in this respect. Attorney Docket No.54926-0014WO1 INFLAMMATION MODULATING PAYLOADS Thus, in some cases, the ARMMs described herein comprise a payload (e.g., as described herein, e.g., a ribonucleoprotein described herein) that is capable of modulating the expression of an inflammatory gene target (or expression product thereof, e.g., mRNA and / or protein). In some cases, the payload comprises molecule(s) capable of decreasing the expression of an inflammatory gene target (e.g., an inflammatory gene target described herein). In some cases, the molecule(s) are capable of increasing the expression of an inflammatory gene target. In some cases, the molecule(s) are capable of editing the inflammatory gene target (or expression product thereof). In some cases, the pay molecule(s) are capable of editing the inflammatory gene target. In some cases, the molecule(s) are capable of editing the gene target so as to increase or decrease the expression of the inflammatory gene target. In some cases, the molecule(s) are capable of editing the inflammatory gene target to cause knock-out or knock-down of the expression of the inflammatory gene target. In some cases, the molecule(s) are capable of editing the inflammatory gene target so as to change the sequence of the expression of the inflammatory gene target. In some cases, the increase or decrease in expression is compared to a reference expression level. In some cases, the reference expression level is the expression level in a control cell, e.g., that has not been delivered the payload. In some cases, the reference expression level is the expression level in cell(s) of an organism (e.g., a patient described herein). In some cases, the cell(s) of the organism are of the same tissue type and / or cell ontology. ADMINISTRATION AND METHODS OF TREATMENT Provided herein are methods of modulating the expression of an inflammatory gene target (e.g., an inflammatory gene target described herein), by administering the ARMMs described herein to a cell, e.g., a cell of a patient described herein. Also provided herein are methods of treatment a disease or disorder associated with mutation and / or dysregulation of an inflammatory gene target (e.g., an inflammatory gene target described herein), by administering the ARMMs described herein to a patient in need thereof (e.g., a patient with or suspected to have the disease or disorder). Also provided herein are methods of delivering the ARMMs described herein to cell(s), methods of inhibiting cytokine release in cell(s), and methods of reducing Attorney Docket No.54926-0014WO1 inflammation in cell(s). In some cases, the cell(s) are phagocyte(s). In some cases, the phagocyte(s) comprise macrophage(s). In some cases, the macrophage(s) are selected from Hofbauer cell(s), anorectum macrophage(s), appendix macrophage(s), colon macrophage(s), elicited macrophage(s), epithelioid macrophage(s), lung macrophage(s), macrophage(s) of medullary sinus of lymph node, tissue-resident macrophage(s), or combinations thereof. In some cases, the elicited macrophage(s) are selected from alternatively activated macrophage(s), inflammatory macrophage(s), suppressor macrophage(s), or combinations thereof. In some cases, the alternatively activated macrophage(s) are kidney interstitial alternatively activated macrophage(s). In some cases, the inflammatory macrophage(s) are kidney interstitial inflammatory macrophage(s). In some cases, the suppressor macrophage(s) are kidney interstitial suppressor macrophage(s). In some cases, the lung macrophage(s) are alveolar macrophage(s). In some cases, the tissue-resident macrophage(s) are selected from Kupffer cell(s), adipose macrophage(s), alveolar macrophage(s), bone marrow macrophage(s), central nervous system macrophage(s), kidney resident macrophage(s), melanophage(s), mesangial phagocyte(s), peritoneal macrophage(s), pleural macrophage(s), secondary lymphoid organ macrophage(s), thymic macrophage(s), and combinations thereof. In some cases, the adipose macrophage is selected from F4 / 80-negative adipose macrophage(s), F4 / 80-positive adipose macrophage(s), and combinations thereof. In some cases, target Kupffer cells are M1 (e.g., classical activation) polarized. In some other cases, target Kupffer cells are M2 (e.g., alternative activation) polarized. In the treatment of certain inflammatory and / or fibrotic liver diseases, the present invention contemplates providing modulating the polarization (i.e., M1 and / or M2) state of Kupffer cells and optionally hepatic stellate cells.In some cases, the central nervous system macrophage(s) are selected from choroid-plexus macrophage(s), meningeal macrophage(s), microgial cell(s), perivascular macrophage(s), and combinations thereof. In some cases, the microgial cell(s) are selected from immature microglial cell(s), mature microglial cell(s), and combinations thereof. In some cases, the secondary lymphoid organ macrophage(s) are selected from lymph node macrophage(s), mucosa-associated lymphoid tissue macrophage(s), splenic macrophage(s), and combinations thereof. In some cases, the lymph node Attorney Docket No.54926-0014WO1 macrophage(s) are selected from lymph node subcapsular sinus macrophage(s), lymph node tangible body macrophage(s), and combinations thereof. In some cases, the mucosa-associated lymphoid tissue macrophage(s) are selected from gut-associated lymphoid tissue macrophage(s), nasal and bronchial associated lymphoid tissue macrophage(s), tonsillar macrophage(s), and combinations thereof. In some cases, the gut-associated lymphoid tissue macrophage(s) are selected from Peyer’s patch macrophage(s), gastrointestinal tract (lamina propria) macrophage(s), tonsillar macrophage(s), and combinations thereof. In some cases, the gastrointestinal tract (lamina propria) macrophage(s) are selected from gastrointestinal tract (lamina propria) macrophage(s) of large intestine, gastrointestinal tract (lamina propria) macrophage(s) of small intestine, and combinations thereof. In some cases, the splenic macrophage(s) are selected from splenic marginal zone macrophage(s), splenic metallophillic macrophage(s), splenic red pulp macrophage(s), splenic white pulp macrophage(s), and combinations thereof. In some cases, the splenic white pulp macrophage(s) are splenic tangible body macrophage(s). In some cases, the thymic macrophage(s) are selected from thymic cortical macrophage(s), thymic medullary macrophage(s), and combinations thereof. Administration The ARMMs can be administered to as subject by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. Attorney Docket No.54926-0014WO1 Disorders Compositions and methods disclosed herein find use in treating diseases or disorders such as inflammatory and autoimmune disorders. In some cases, the disorder is selected from Allergic asthma, allergic rhinitis, chronic rhinosinusitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, atopic dermatitis, eosinophilic pneumonia, Crohn's disease, ulcerative colitis, psoriasis, rheumatoid arthritis (RA), primary Sjogren's syndrome, systemic sclerosis, gout, ankylosing spondylitis, pustular psoriasis, systemic lupus erythematosus (SLE), adult-onset Still's disease, Bechet’s disease, IgG4-related disease, cancer, MS, type1 diabetes, Sjogren's syndrome, atherosclerosis, acute respiratory distress syndrome (ARDS), acute lung injury, migraine, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, ischemic heart disease, diabetes, insulin-resistant diabetes, COVID- 19, osteoarthritis, osteoporosis, ischemia-related neuronal death, excitotoxic neuronal injury, diabetes mellitus, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, lupus erythematosus, primary biliary cholangitis, Sjögren's syndrome, steroid- resistant asthma, allergic contact dermatitis, non-atopic eczema, dyslipidemia, diabetes, traumatic brain injury, ALS, Familiar cold-associated autoinflammatory syndrome, Muckle-Wells syndrome, urate crystal-induced peritonitis, acute myocardial infarction, psoriasis-like dermatitis, diabetic nephropathy, Stargardt disease type 1, atrial fibrillation, acute liver injury, nonalcoholic steatohepatitis (NASH), cirrhosis, cystic fibrosis, rheumatoid arthritis, celiac disease, asymmetrical septal hypertrophy (ASH), Silicosis, ischemia reperfusion, smoke / chemical injury, metal overload syndromes, Metabolic syndrome, type 2 diabetes, peripheral artery disease, renal disease, ulcerative colitis, myocardial ischemia / reperfusion injury, myocarditis, renal ischemia / reperfusion injury, renal fibrosis, diabetic kidney disease, periodontal disease, Minimal change disease, focal segmental glomerulosclerosis, graft-versus-host disease, polyarticular juvenile idiopathic arthritis, Hashimoto's thyroiditis, Grave's disease, Addison's disease, myasthenia gravis, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, polymyositis, scleroderma, Pulmonary alveolar proteinosis, interstitial lung disease, aortic aneurysm, obesity, axial spondyloarthritis, myelofibrosis, liver fibrosis, skin fibrosis, idiopathic pulmonary fibrosis, juvenile idiopathic arthritis, noninfectious uveitis, adult-onset Still's disease, Attorney Docket No.54926-0014WO1 giant cell arteritis, Takayasu arteritis, Castleman disease, cytokine release syndrome, uveitis, thyroid eye disease, erosive hand osteoarthritis, schizophrenia, Schnitzler syndrome, myocardial infarction, familiar Mediterranean fever, COVID-19 pneumonia, systemic scleroderma, myositis, pulmonary fibrosis, Aicardi-Goutières syndrome, COPA syndrome, and combinations thereof. In some cases, e.g., when the treatment target is NLRP3, the disorder is selected from familiar cold-associated autoinflammatory syndrome, Muckle-Wells syndrome, urate crystal-induced peritonitis, acute myocardial infarction, gout, psoriasis-like dermatitis, diabetic nephropathy, SLE, Stargardt disease type 1, Alzheimer's disease, atherosclerosis, atrial fibrillation, osteoarthritis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, cystic fibrosis, rheumatoid arthritis, ARDS, celiac disease, ASH, Silicosis, ischemia reperfusion, smoke / chemical injury, metal overload syndromes, and combinations thereof. In some cases, e.g., when the treatment target is IRF-5, the disorder is selected from Sjogren's syndrome, rheumatoid arthritis, SLE, systemic scleroderma, multiple sclerosis, myositis, ulcerative colitis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, ARDS, and combinations thereof. In some cases, e.g., when the treatment target is GSDMD, the disorder is selected from Familiar cold-associated autoinflammatory syndrome, Muckle-Wells syndrome, urate crystal-induced peritonitis, acute myocardial infarction, gout, psoriasis-like dermatitis, diabetic nephropathy, SLE, Stargardt disease type 1, Alzheimer's disease, atherosclerosis, atrial fibrillation, osteoarthritis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, cystic fibrosis, rheumatoid arthritis, ARDS, celiac disease, ASH, Silicosis, ischemia reperfusion, smoke / chemical injury, metal overload syndromes, and combinations thereof. In some cases, e.g., when the treatment target is ASC, the disorder is selected from Familiar cold-associated autoinflammatory syndrome, Muckle-Wells syndrome, urate crystal-induced peritonitis, acute myocardial infarction, gout, psoriasis-like dermatitis, diabetic nephropathy, SLE, Stargardt disease type 1, Alzheimer’s disease, atherosclerosis, atrial fibrillation, osteoarthritis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, cystic fibrosis, rheumatoid arthritis, ARDS, celiac disease, ASH, Silicosis, ischemia reperfusion, smoke / chemical injury, metal overload syndromes, and combinations thereof. Attorney Docket No.54926-0014WO1 In some cases, e.g., when the treatment target is STING, the disorder is selected from SLE, Aicardi-Goutières syndrome, COPA syndrome, Alzheimer disease, Parkinson disease, ALS, and combinations thereof. In some cases, e.g., when the treatment target is IL-12, the disorder is selected from Crohn's disease, ulcerative colitis, psoriasis, diabetes mellitus, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, lupus erythematosus, primary biliary cholangitis, Sjögren's syndrome, and combinations thereof. In some cases, e.g., when the treatment target is IL-10, the disorder is selected from Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, allergic asthma, steroid-resistant asthma, allergic contact dermatitis, non-atopic eczema, dyslipidemia, diabetes, atherosclerosis, MS, traumatic brain injury, ALS, Alzheimer's disease, Parkinson's disease, and combinations thereof. In some cases, e.g., when the treatment target is TNF-alpha, the disorder is selected from Rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis, psoriasis, noninfectious uveitis, ankylosing spondylitis, and combinations thereof. In some cases, e.g., when the treatment target is IL-6, the disorder is selected from Rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, giant cell arteritis, Takayasu arteritis, Castleman disease, SLE, systemic sclerosis, cytokine release syndrome, uveitis, thyroid eye disease, erosive hand osteoarthritis, schizophrenia, Schnitzler syndrome, myocardial infarction, familiar Mediterranean fever, COVID-19 pneumonia, and combinations thereof. In some cases, e.g., when the treatment target is MCP-1, the disorder is selected from Alzheimer's disease, Parkinson's disease, epilepsy, MS, atherosclerosis, stroke, ischemic heart disease diabetes, insulin-resistant diabetes, COVID-19, osteoarthritis, RA, osteoporosis, allergic asthma, ischemia-related neuronal death, exitotoxic neuronal injury, and combinations thereof. In some cases, e.g., when the treatment target is IL-33, the disorder is selected from Allergic asthma, allergic rhinitis, chronic rhinosinusitis, COPD, pulmonary fibrosis, atopic dermatitis, eosinophilic pneumonia, Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, RA, primary Sjogren's syndrome, systemic sclerosis, gout, ankylosing spondylitis, pustular psoriasis, SLE, adult-onset Still's disease, Behcet's disease, IgG4-related disease, and combinations thereof. Attorney Docket No.54926-0014WO1 In some cases, e.g., when the treatment target is TGF-beta, the disorder is selected from Pulmonary fibrosis, myelofibrosis, liver fibrosis, NASH, skin fibrosis, renal fibrosis, idiopathic pulmonary fibrosis, cancer, and combinations thereof. In some cases, e.g., when the treatment target is IL-27, the disorder is selected from Allergic asthma, allergic rhinitis, cancer, MS, type 1 diabetes, Sjogren's syndrome, Crohn's disease, ulcerative colitis, atherosclerosis, and combinations thereof. In some cases, e.g., when the treatment target is GM-CSF, the disorder is selected from Pulmonary alveolar proteinosis, RA, osteoarthritis, MS, Crohn's disease, ulcerative colitis, interstitial lung disease, aortic aneurysm, allergic asthma, obesity, COVID-19, psoriasis, axial spondylarthritis, ankylosing spondylitis, and combinations thereof. In some cases, e.g., when the treatment target is PU.1, the disorder is selected from Pulmonary alveolar proteinosis, Grave's disease, Hashimoto's thyroiditis, MS, RA, psoriatic arthritis, psoriasis, systemic sclerosis, SLE, Sjogren's syndrome, primary biliary cirrhosis, type 2 diabetes, Alzheimer's disease, Parkinson's disease, allergic asthma, and combinations thereof. In some cases, e.g., when the treatment target is PPARgamma, the disorder is selected from Pulmonary alveolar proteinosis, Grave's disease, Hashimoto's thyroiditis, MS, RA, psoriatic arthritis, psoriasis, systemic sclerosis, SLE, Sjogren's syndrome, primary biliary cirrhosis, type 2 diabetes, Alzheimer's disease, Parkinson's disease, allergic asthma, and combinations thereof. In some cases, e.g., when the treatment target is NOS, the disorder is selected from Allergic asthma, ARDS, acute lung injury, RA, Alzheimer's, Parkinson's, pulmonary fibrosis, atherosclerosis, migraine, and combinations thereof. In some cases, e.g., when the treatment target is Lipoxin A4, the disorder is selected from Metabolic syndrome, type 2 diabetes, peripheral artery disease, renal disease, COPD, Crohn's disease, ulerative colitis, RA, cancer, Alzheimer's disease, stroke, atherosclerosis, myocardial ischemia / reperfusion injury, myocarditis, acute lung injury, allergic asthma, pulmonary fibrosis, cystic fibrosis, renal ischemia / reperfusion injury, renal fibrosis, diabetic kidney disease, periodontal disease, and combinations thereof. In some cases, e.g., when the treatment target is CD86, the disorder is selected from Minimal change disease, focal segmental glomerulosclerosis, psoriasis, psoriatic Attorney Docket No.54926-0014WO1 arthritis, RA, graft-versus-host disease, polyarticular juvenile idiopathic arthritis, type 1 diabetes, MS, SLE, Hashimoto's thyroiditis, Grave's disease, Addison's disease, Crohn's disease, ulcerative colitis, myastenia gravis, sympathetic ophtalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, Sjogren's syndrome, polymyositis, scleroderma, and combinations thereof. In some cases, e.g., when the treatment target is CD80, the disorder is selected from Minimal change disease, focal segmental glomerulosclerosis, psoriasis, psoriatic arthritis, RA, graft-versus-host disease, polyarticular juvenile idiopathic arthritis, type 1 diabetes, MS, SLE, Hashimoto's thyroiditis, Grave's disease, Addison's disease, Crohn's disease, ulcerative colitis, myastenia gravis, sympathetic ophtalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, Sjogren's syndrome, polymyositis, scleroderma, and combinations thereof. Patients Suitable patients for the compositions and methods herein include those who are suffering from, who have been diagnosed with, or who are suspected of having an inflammatory or autoimmune disorder, e.g., a disorder described herein. In some embodiments, the methods of treatment provided herein may be used to treat a subject (e.g., human, monkey, dog, cat, mouse) who has been diagnosed with or is suspected of having an inflammatory or autoimmune disorder, e.g., a disorder described herein. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the patient is or has been diagnosed with an inflammatory or autoimmune disorder, e.g., a disorder described herein. EXAMPLES The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. Attorney Docket No.54926-0014WO1 Example 1: Functional Delivery of Cas9 / gRNA Ribonucleoprotein (RNP) by ARMMs to Multiple Cell Types ARMMs loaded with Cas9 / gRNA complexes were prepared as shown in FIG. 1. As shown in FIG.2, ARMMs delivered functional Cas9 / gRNA ribonucleotprotein (RNP) to multiple cell types, resulting in the high efficiency disruption of multiple genomic targets. Example 2: ARMMs Loaded with Cas9 / gRNA RNP Enable Editing of Immune Modulation Targets in Macrophages in vitro and in vivo To investigate the potential of using ARMMs carrying Cas9 RNPs in diseases where macrophages play a crucial role, experiments were conducted to evaluate the targeting efficacy of ARMMs on mouse inflammatory genes Nlrp3 and Irf-5. The NLRP3 protein, along with procaspase-1 and ASC, is a key component of the NLRP3 inflammasome that plays an essential role in shaping immune responses and regulating the integrity of intestinal homeostasis in many common inflammatory diseases. Similarly, IRF5 plays a crucial role in controlling both acute and chronic inflammation. To knock out the Nlrp3 gene, we designed two approaches: one targeting its promoter region to knock out the NFkB response element, which could inhibit the upregulation of Nlrp3 protein expression at stimulation but keep its basic expression level as needed, and the other targeting its exon region to completely knock out Nlrp3 protein expression (two approaches schematized in FIG.3, top). Different guide RNAs (gRNAs) were designed to target these two loci in the mouse Nlrp3 gene and the editing efficiency was tested by transiently transfecting a plasmid encoding ARRDC1-Cas9 and a plasmid encoding each of the gRNAs described in Table 6 into mouse neuro2a cells. Percent (%) indel formation for various gRNAs are shown in the plot of FIG.3. Table 6. NLRP3 targeting gRNA sequences SEQ ID NO: Labe on X- i f FIG 3 h NHP Attorney Docket No.54926-0014WO1 SEQ ID NO: 3 Nlrp-g2 Nlrp3-#30GGCCTTTGACGAGCACATTGmSEQ ID NO: 4 Nlrp-g3 Attorney Docket No.54926-0014WO1 SEQ ID NO: 30 N / A NLRP3-h-P1-2GAGTGAGGGAAGTGAAACTAhSEQ ID NO: 31 N / A sequence SEQ ID NO: 10), ARMMs were generated and their editing efficiency was tested by applying them onto the mouse macrophage cell line RAW264.7 cells. This resulted in good knockout efficiency, as evidenced by indels in the target locus, with an EC50 of approximately 7x10^4 ARMMs / cell (FIG.4). Intranasal injections in mice were also carried out with these ARMMs, which resulted in approximately 50% knocking out with one dose and 60% knocking out with two doses separated by 30 minutes (FIG.5). Further ARMMs carrying another gRNA (Nlrp3-#11, comprising spacer sequence SEQ ID NO: 1) that targets the exon of Nlrp3 were generated. With these ARMMs, Nlrp3 was directly knocked out in RAW264.7 cells and Bone-marrow- derived macrophage (BMDM) (FIG.6). With LPS and NIG stimulation, there was no Nlrp3 protein upregulation as in the WT control. Additionally, the cytokine release was tested with these BMDM and found that the release of IL-1b was completely inhibited from the BMDM pretreated with ARMMs for knocking out Nlrp3 (FIG.7). In vivo testing of these ARMMs was carried out. After the intranasal injection, the indels for the Nlrp3 gene from these alveolar macrophages was analyzed, and it showed approximately 40-50% knocking out efficiency (FIG.8). Similarly, for the Irf-5 gene, ARMMs were generated with a gRNA targeting its exon region. The gRNA targeting an exon of the Irf-5 included a spacer sequence GGCTTCAGCCTCACACGGCG (SEQ ID NO: 115). Applying these ARMMs onto RAW264.7 cells completely knocked out Irf-5 gene expression (FIG.9), which also blocked the INFbeta release with LPS stimulation (FIG.10). Approximately 50% indels of the Irf-5 gene from the alveolar macrophages in the in vivo intranasal injection were detected (FIG.11). Attorney Docket No.54926-0014WO1 Molecular cloning and plasmids ARRDC1-Cas9 expression construct was made by cloning full-length DNA fragment of wild-type ARRDC1 and Cas9 with the G4S linker at the C-terminus of ARRDC1 into the pcDNA3.1(+) vector at Vectorbuilder. ARRDC1-CRE constructs were made in the pLV vector with CMV promoter and puromycin selection marker at Vectorbuilder, and the relative lentivirus was also made by Vectorbuilder. ARRDC1- mCherry construct was made in the JumpIn vector with puromycin selection marker at Vectorbuilder. All the other gRNA plasmids were made by Vectorbuilder. New constructs were confirmed by direct DNA sequencing. Cell culture HEK293T cells (ATCC; CRL-3216), NIH3T3 cells (ATCC; CRL-1658), Raw264.7 cells (ATCC; TIB-71) and sNF02.2 cells (ATCC; CRL-2885) were maintained in DMEM (ATCC; Catalog No.30-2002) supplemented with 10% (v / v) heat-inactivated fetal bovine serum (FBS). Neuro-2a cells (ATCC; CCL-131) were maintained in EMEM (ATCC; Catalog No.30-2003) supplemented with 10% (v / v) heat-inactivated FBS. A549 cells (ATCC; CCL-185) were maintained in F-12K Medium (ATCC; Catalog No.30-2004) supplemented with 10% (v / v) heat- inactivated FBS. All cell lines were sub-cultured twice per week at the split ratio of 1:3 – 1:20, adjusted based on cell types and cell density. Cells were cultured at 37 °C with 5% carbon dioxide and were confirmed to be negative for mycoplasma by testing with MycoStrip™ - Mycoplasma Detection Kit (InvivoGen; rep-mys-50) or Myco- Sniff Mycoplasma PCR Detection Kit (MP Biomedicals; 093050201). Expi293 suspension culture was maintained in Expi293 Expression Medium (Thermo Fisher Scientific, A1435102) (Thermo Fisher, Waltham, MA) at 37 °C with 5% carbon dioxide on a rotator at 250 rpm. Cells were sub-cultured twice per week with seeding density of 0.5-1x106cells / mL. ARMMs Production and Purification Expi293 stable cells expressing A1-GFP or A1-mCherry were seeded at a density of 0.5x106viable cells per mL and expanded for 4-5 days to a VCD of ~5x106 / mL. Cells and large cellular debris were removed by centrifugation steps at 500 x G for 3 minutes and 2000 x G for 10 minutes, respectively. The clarified Attorney Docket No.54926-0014WO1 conditioned media (CM) were then 0.2 µm filtered and stored at 4 °C until downstream processing. Other ARMMs were produced by transiently transfecting wild type Expi293 cells using Expifectamine (Fisher Scientific A14524) according to the manufacturer’s recommendations, omitting the Enhancer. Cells were transfected at a density of 3x106 / mL and allowed to recover overnight. The next day, cells were pelleted and re- suspended in fresh medium. Medium was conditioned for 3 days before clarification and storage as with the stable cells’ CM. To purify the ARMMs, the CM was processed by tangential flow filtration (TFF) followed by ultracentrifugation. TFF was done on a Repligen KR2i system using a mPES hollow fiber filter with a 300 kD molecular weight cutoff, either microKros or midiKros format. The material was concentrated 5 times and washed with 5 continuous diavolumes of PBS, then further concentrated up to 15x. The retentate was 0.2 µm filtered, and then ultracentrifuged at 100,000 x G for 2h at 4 °C in a Beckman Coulter Optima XE-90 ultracentrifuge using the swinging bucket rotor SW32 Ti. The supernatant was decanted and the tube briefly rested upside down to remove supernatant from the sides of the tube. Then the pellet was re-suspended in 200-500 µl PBS and sterile filtered twice using a syringe filter (Millipore Sigma’s Millex-GV PVDF 13 mm 0.2 µm filter, #slgv013sl). ARMMs were stored at 4 °C. (MilliporeSigma, Burlington, MA). To quantify the concentration and size of particles, NTA was done using the Particle Metrix Zetaview with the following settings: Sensitivity 82.4, shutter 100, minimum area 10, maximum area 3000, and minimum brightness 20. The particles were diluted in distilled water such that there were 50 – 200 on the screen, which is within the instrument’s linear range of detection. The concentration of GFP and mCherry in the ARMMs was determined using Abcam’s SimpleStep ELISA kits (ab171581 and ab221829) using the same instructions as for lysing non-adherent or detached cells, but omitting the centrifugation steps (Abcam, Waltham, MA). The ARMMs were diluted into the 1X cell extraction buffer at dilutions of 1:50 to 1:100000, depending on concentration. Mouse BMDM ARMM A1-Cre Uptake Assay Procedure Ai 14 mouse fresh collected bone marrow cells were flushed from the femur and tibias with PBS, filtered through 40um cell strainer, and cultured in DMEM Attorney Docket No.54926-0014WO1 (Gibco Catalog #10-564-011) (Thermo Fisher Scientific, Waltham, MA) containing 10% HI FBS (Gibco Catalog #10082147) and 50ng / ml M-CSF (R&D Systems Catalog # 416-ML-010) for 7 days (R&D Systems, Minneapolis, MN). Primed BMDM (Bone Marrow Derived Macrophage) were re-plated 5,000 cells per well medium in 96 well microplate and let cells recovery for overnight. Next morning, ARMM A1-Cre were prepared in pre-warmed growth medium at designed concentrations. All mediums were removed from 96 well cell plate and cells were treated with 100ul of diluted ARMM solutions. Cell plate was incubated at 37 °C CO2incubator for 24h. Then cells were fixed with 4% Paraformaldehyde (Alfa Aesar Cat#43368-9M) at room temperature for 10 minutes and stained with Hoestch (Invitrogen Cat# H3570) at 2µg / ml at room temperature for 15 minutes. Fixed cells were washed with 250µl 1x PBS 2 times. Then cell plate was ready for imaging analysis on the ImageXpress Nano Automated Image system. ARMMs uptake and CRISPR / Cas9 genome editing evaluation Cells were seeded in 96-well plates at the densities of 5000 cells / well for cell lines or 10,000 cells / well for mouse primary cells. After 3 hours, ARMMs were applied to cells at the indicated concentrations (ARMMs / cell). Cells treated for 96 hours were collected for genomic DNA (gDNA) extraction or stored at -80 °C for later processing. gDNA was extracted using the DNeasy 96 Blood & Tissue Kit (Qiagen, 69581) and following the manufacturer’s instructions (Qiagen, Cambridge, MA). Targeted PCR was performed to amplify the genomic regions harboring the genome editing sites.5 µL of gDNA solution was used as template in the 50 µL PCR reaction using Q5 High-Fidelity 2X Master Mix (NEB, M0492) with the manufacturer’s protocols. PCR products were confirmed on E-gels and purified using the QIAquick 96 PCR Purification Kit (Qiagen, 28181).1-5 µL of the eluted PCR products were submitted for Sanger sequencing to have an initial evaluation of editing before the rest of PCR products were submitted for Amplicon deep sequencing. Mouse dosing and tissue collection Mice were dosed oral-tracheally with 50uL of solution containing 5x1011ARMMs particles or 50uL of Phosphate Buffered Saline (PBS). Briefly, mice were anesthetized via isoflurane, and front teeth (incisors) placed over a silk suture suspended across an angled platform to facilitate access to the oral cavity. The tongue Attorney Docket No.54926-0014WO1 was pulled from the oral cavity using blunt forceps to prevent the swallowing reflex and the nose of the mouse was covered to facilitate inhalation through the mouth. 50uL of test article solution was then pipetted into the mouse’s mouth. The mouse was held in the described position until an audible inhalation through the mouth was heard. The mouse was returned to its cage and monitored until waking from anesthesia. For mCherry-payloaded ARMMs administration, lungs were collected from mice two hours after administration for downstream processing. For administration of Cre-payloaded ARMMS, lungs were collected from mice 96 hours after administration for downstream processing. Isolation of lung tissue for flow cytometry analysis Single cell suspensions from lung were generated following the protocol published by Nakano et al.2018 (DOI: 10.1007 / 978-1-4939-7896-0_6). Briefly, lungs were inflated in situ with 1mL of digest media #1 (RPMI (Gibco 12633-012) containing 4 U / mL elastase (Worthington #LS002290), 1 U / mL Dispase (Sigma #D4693), and 200 ug / mL DNAse (Sigma #10104159001)) using a gavage adaptor for a 1-mL syringe and trachea clamped to prevent leaking. The lung was excised from the mouse and placed into 2-mL of digest media #1 for 30min in a 37 °C water bath. The lung was then removed from the digest media and cut into small pieces followed by a second digestion step in digest media #2 (5mL RMPI, 25µg / mL liberase (Sigma 05401020001) and 200µg / mL DNAse) for 30 min in a 37 °C incubator. The cell suspension was then filtered through a 70 µm cell strainer and pelleted at 400 x G for 5 min at 4 °C followed by RBC lysis using ACK lysis buffer (Gibco A10492-01) for 5 minutes on ice before proceeding with flow cytometry staining. Approximately 5x105to 1x106cells were used for flow cytometry staining. Prior to antibody staining, live / dead fixable near IR (Thermo Fisher L10119) staining was carried out according to manufacturer’s instructions. Alveolar macrophages were identified as CD45+ CD11bint CD11Chi SiglecF+. The following antibodies were used at a 1:100 dilution in Flow Cytometry Staining Buffer (eBiosciences #00-4222- 26): CD45-PerCP Cy5.5 (BioLegend 103132), (BioLegend, San Diego, CA) CD11b- Alexafluor 488 (Thermo Fisher 53-0112-82), CD11c-APC (BioLegend 117310), and SiglecF-PE / Cy7 (BioLegend 155527). mCherry or tdTomato intensity in the alveolar macrophage population was evaluated by native fluorescence. mCherry or tdTomato Attorney Docket No.54926-0014WO1 positive cells were gated based on mice administered PBS in place of ARMMs as a negative control. Flow cytometry was performed on an Attune NxT flow cytometer, and data analysis performed on FCS Express (version 7). Bone Marrow Derived Macrophages (BMDM) were isolated by isolating the tibia and fibula from both hind legs of the mouse, gently cutting the end of the bone to expose the marrow, and a brief centrifugation to release the marrow. Cells were cultured in the presence of 50 ng / mL m-CSF cultured in DMEM (GIBCO Cat#10- 564-011) containing 10% heat-inactivated FBS (GIBCO Cat#10082147) and 50 ng / mL M-CSF (R&D Systems Cat# 416-ML-010) for 7 days. Primed BMDM (Bone Marrow Derived Macrophage) were re-plated 5,000 cells per well medium in 96 well microplate and let cells to recover for overnight. Next morning, ARMMs loaded with Cas9 / NLRP3 gRNA or ARMMs without payload were prepared in pre-warmed growth medium at designed concentrations. All mediums were removed from 96 well cell plate and cells were treated with 100 µl of diluted ARMM solutions. Cell plate was incubated at 37°C CO2 incubator for 96 hours. For inflammasome activation, BMDM or RAW264.7 macrophage cell line were treated with 1 ng / mL lipopolysaccharide (LPS) (Sigma-Aldrich L2630) for 24 hours then treated with 1 µM nigericin (NIG) (Invivogen tlrl-nig). Supernatant from cell cultures were passed through 0.22 µm filter and stored until further cytokine production analysis. Whole cell lysates were created through NP40 cell lysis buffer (Fisher Scientific FNN0021) digestion according to manufacturer’s protocols and run on SDS-PAGE with Jess Simple Western System (R&D System 004-650) analysis of NLRP3 and actin protein content using antibodies against NLRP3 (Cell Signaling Technologies 15101S) and beta-actin (Thermo Scientific AM4302). Mouse cytokine release assay Collected conditional medium or fluid from mice were prepared following protocol instruction: R&D Systems Mouse IL-1 beta / IL-1F2 Quantikine ELISA Kit, MLB00C or BioLegend LEGENDplex™ Mouse Inflammation Panel (13-plex) with Filter Plate. Attorney Docket No.54926-0014WO1 Example 3: High Efficiency Oral-Tracheal Functional Delivery of Cre-payloaded ARMMs in mice As ARMMs.Cre.P showed strong functional delivery to primary lung macrophages ex vivo at a wide range of doses (FIG.12), functional delivery of ARMMs.Cre.P in vivo was tested using local administration to the lung. A single dose of 5x1011ARMMs.Cre.P was delivered oral-tracheally to Cre-reporter mice. Functional delivery of Cre is represented by the initiation of tdTomato expression in target cells (FIG.12). Four days after ARMMs.Cre.P administration, lungs were harvested and tdTomato signal was assessed in alveolar macrophages as schematized in FIG.13A. Alveolar macrophages (identified as CD45+CD11bmidCD11C+SiglecF+), isolated from Cre-reporter mice revealed robust tdTomato signal in ARMMs.Cre.P-treated mice as determined by flow cytometry (FIG.13B, right panel) in comparison to PBS-treated control mice (FIG.13B, left panel), with ~50-80% of isolated alveolar macrophages displaying tdTomato signal (FIG.13C). tdTomato positive cells showing in all five lung lobes (FIG.13D). The histology data also shown revealed strong co-localization of tdTomato positive cells with lung macrophage marker CD206 in ARMMs.Cre.P-treated mice (FIG.13E lower panels), with no tdTomato signal apparent in PBS-treated controls (FIG.13E upper panels). Consistent with the biodistribution of ARMMs.Cre.P, delivery of fluorescent protein payload mCherry via ARMMs.mCherry.P (FIG.14A) showed strong uptake in the alveolar macrophage population 2-hours after oral-tracheal administration by flow cytometry, with ~50-75% of alveolar macrophages displaying positive mCherry signal (FIG.14B, FIG.14C). Histological assessment of paraffin embedded lung cross-sections showed strong mCherry antibody staining in CD206+ alveolar macrophages. Furthermore, mCherry protein remained detectable in alveolar macrophages by histology through 48-hours after administration (FIG.14D). Alveolar macrophages isolation and culture: Alveolar macrophages were isolated by lung digestion as previously described (see isolation of lung tissue for flow cytometry analysis) followed by selection with CD11c microbeads (Miltenyi 130-125-835) according to manufacturer’s instructions. Attorney Docket No.54926-0014WO1 Macrophages were plated at 2E4 cells in 96-well tissue culture plates and cultured in DMEM with 10% FBS. Mouse Strains and housing Female C57BL / 6 mice (6-8week) were purchased from Charles River Laboratories, and Female Ai9 (Strain #:007909) or Ai14 (Strain #:007908), 6-8 weeks old mice were purchased from Jackson Labs (Strain #:007909, 6-8 week), Animal use and care was in accordance with institutional guidelines. Mice were held in the Charles River Vivarium (Cambridge, MA). They were fed standard chow (commercially prepared complete diet) and had food and water access ad libitum. All animal experiments were approved by the Animal Care and Use Committee of Charles River. Mouse dosing and tissue collection Mice were dosed oral-tracheally with 50uL of solution containing 5x1011ARMMs particles or 50uL of Phosphate Buffered Saline (PBS). Briefly, mice were anesthetized via isoflurane, and front teeth (incisors) placed over a silk suture suspended across an angled platform to facilitate access to the oral cavity. The tongue was pulled from the oral cavity using blunt forceps to prevent the swallowing reflex and the nose of the mouse was covered to facilitate inhalation through the mouth. 50uL of test article solution was then pipetted into the mouse’s mouth. The mouse was held in the described position until an audible inhalation through the mouth was heard. The mouse was returned to its cage and monitored until waking from anesthesia. For administration of Cre-payloaded ARMMS, lungs were collected from mice 96-hrs after administration for downstream processing. Processing of samples for Histology and immunofluorescence staining of tissue sections: Lungs were isolated and each lobe separated individually and fixed in 4% PFA overnight at 4 °C. For paraffin processing, samples were transferred to 70% ethanol and processed by Alamak Biosciences (Beverly, MA) and sectioned at 5 µm thickness. For Frozen section processing, samples were transferred from 4% PFA to 15% sucrose for 8 hours, followed by a transfer to 30% sucrose overnight at 4 °C. Tissues were then embedded in Optimal Cutting Temperature media (Tissue-Tek Attorney Docket No.54926-0014WO1 O.C.T) and sectioned on a Leica CM1860 cryostat at 10µm thickness and stored at - 80 °C. For histology, left lobes from the mice were assessed for payload delivery. For immunofluorescence staining of paraffin embedded tissues, sections were deparaffinized in Xylene for 2 washes of 10 min, followed by a descending series of alcohol washes of 100%, 95%, 70%, and 50% ethanol followed by two washes in water. Antigen retrieval was then performed using Vector Labs citrate-based antigen unmasking solution (Vector Labs H3300) according to manufacturer’s instructions. Frozen sections were dried at room temperature for 20 min and washed in PBS for an additional 10 mins. Both paraffin and frozen sections were then permeabilized in 0.4% Triton-X in Phosphate-buffered saline. Sections were briefly washed in PBS followed by 1-hr incubation with animal free blocking media (Vector Labs SP-5035). Sections were once again washed in PBS before incubation with primary antibody overnight at 4C. Primary antibodies used were rabbit-CD206 (Cell Signaling 24595S) and chicken-mCherry (Aves MCHERRY-0100) at 1:250 dilution in PBS. Sections were washed three times with PBS for 10 min each, followed by incubation with secondary antibody for 2-hrs at room temperature. Secondary antibodies used were Goat anti Chicken AlexaFluor 488 (Abcam ab15069) and Goat anti rabbit Alexafluor 647 (Abcam ab150075). Samples were washed three times for 10 min each in PBS before mounting with Vectashield Plus antifade mounting media with DAPI (Vectorlabs #H-2000). Images were taken on an EXC-500 microscope (Accu-scope) fitted with a DHYANA CMOS camera for fluorescent imaging (TUCSEN) and recorded using Mosaic imaging software (Tucsen, version 1.6). Isolation of lung tissue for flow cytometry analysis Single cell suspensions from lung were generated following the protocol published by Nakano et al.2018 (DOI: 10.1007 / 978-1-4939-7896-0_6). Briefly, lungs were inflated in situ with 1mL of digest media #1 (RPMI (Gibco 12633-012) containing 4 U / mL elastase (Worthington #LS002290), 1 U / mL Dispase (Sigma #D4693), and 200 ug / mL DNAse (Sigma #10104159001)) using a gavage adaptor for a 1-mL syringe and trachea clamped to prevent leaking. The lung was excised from the mouse and placed into 2-mL of digest media #1 for 30 min in a 37 ℃ water bath. The lung was then removed from the digest media and cut into small pieces followed by a second digestion step in digest media #2 (5mL RMPI, 25µg / mL liberase (Sigma Attorney Docket No.54926-0014WO1 05401020001) and 200µg / mL DNAse) for 30 min in a 37 ℃ incubator. The cell suspension was then filtered through a 70µm cell strainer and pelleted at 400 x G for 5 min at 4 ℃ followed by RBC lysis using ACK lysis buffer (Gibco A10492-01) for 5 min on ice before proceeding with flow cytometry staining. Approximately 5x105to 1x106cells were used for flow cytometry staining. Prior to antibody staining, live / dead fixable near IR (Thermo Fisher L10119) staining was carried out according to manufacturer’s instructions. Alveolar macrophages were identified as CD45+ CD11bint CD11Chi SiglecF+. The following antibodies were used at a 1:100 dilution in Flow Cytometry Staining Buffer (eBiosciences #00-4222- 26): CD45-PerCP Cy5.5 (BioLegend 103132), CD11b-Alexafluor 488 (Thermo Fisher 53-0112-82), CD11c-APC (BioLegend 117310), and SiglecF-PE / Cy7 (BioLegend 155527). mCherry or tdTomato intensity in the alveolar macrophage population was evaluated by native fluorescence. mCherry or tdTomato positive cells were gated based on mice administered PBS in place of ARMMs as a negative control. Flow cytometry was performed on an Attune NxT flow cytometer, and data analysis performed on FCS Express (version 7). Example 4: Evaluation of In Vivo Genome Edited Alveolar Macrophages by NLRP3 Stimulation Mice were administered ARMMs loaded with Cas9 / NLRP3 gRNA (Nlrp3- #start3) intranasally. The gRNA used in this experiment comprised spacer sequence SEQ ID NO: 8. On day 4, the study was terminated. Bronchoalveolar lavage (BAL) was collected from animals and cells were isolated. Cells were seeded at 7.5x104cells / well, and cultured in medium supplemented with mouse M-CSF (macrophage stimulating factor) overnight. NLRP3 inflammasome activity was stimulated by treatment with LPS and Nigericin. Conditioned media (CM) were evaluated by ELISA for IL-1beta levels and cell lysates were evaluated for NLRP3 protein analysis. As shown in FIGs.15A and 15B, stimulation of the NLRP3 inflammasome was suppressed after treatment with ARMMs targeting disruption of NLRP3. Attorney Docket No.54926-0014WO1 Example 5: Cas9 Payloaded ARMMs Targeting NLRP3 to Kupffer Cells Demonstrate In Vivo Genetic Editing Acute liver injury (ALI) can be initiated through a variety of stimuli and is recognized as serving as a precursor to many chronic liver diseases. The present invention contemplates that NLRP3 inflammasome plays a central role in ALI to exacerbate liver disease pathogenesis thus making NLRP3 a potential target for therapeutic intervention. This Example describes ARMMs loaded with functional Cas9 and gRNA targeting NLPR3 effectively knocks out NLRP3 in liver Kupffer cells of treated mice. A single administration of 1012particles (200 µL of 5x1012particles / mL) of Cas9 and gRNA payloaded ARMMs targeting NLRP3 (Nlrp3-#start3 comprising spacer sequence SEQ ID NO: 8) or PBS vehicle control were delivered via standard retro-orbital injection to two groups of seven (7) each C57BL / 6 male mice (6-8wk), Charles River, in single efficacy study to assess effects in acute liver injury. These groups of mice were administered three days prior to chemical insult of 2 µl / g body weight carbon tetrachloride (CCl4) to elicit liver injury. A group of seven (7) C57BL / 6 male mice were also given 10 mg / kg small molecule NLPR3 inhibitor sodium;1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl-[4-(2-hydroxypropan- 2-yl)furan-2-yl]sulfonylazanide (“MCC950”) delivered via intraperitoneal injection 1 hour prior to CCl4. (study design schematized in FIG.16). Mice were euthanized one day after CCl4treatment to assess their inflammation. Serum samples were analyzed for liver damage markers AST and ALT (FIGs. 17A and 17B). Functional delivery of Cas9 was assessed by deep sequencing of the NLRP3 locus in F4 / 80+ MACS purified cells from dissected livers of treated mice (predominantly Kupffer cells in a healthy animal). ARMMs payloaded with Cas9 and guide RNAs targeting NLRP3 demonstrate genomic editing efficiency. (FIG.18). Isolation of mouse liver tissue for flow cytometry analysis To isolate liver cells including hepatocytes, Kupffer cells and liver sinusoidal endothelial cells (“LSEC”), parenchymal, and non-paranchymal liver cells were isolated by two-step liver perfusion. Briefly, livers were perfused through the inferior vena cava with 1mM EDTA, 25mM HEPES in PBS followed by perfusion with Attorney Docket No.54926-0014WO1 1mg / mL Collagenase IV (Sigma C428-100MG) in DMEM. Livers were then excised from the mouse and nicked to release cells. Cell suspension was then filtered through a 70um cell strainer. Staining with live / dead fixable near IR (Thermo Fisher L10119) staining was carried out according to manufacturer’s instructions. Results of these experiments are shown in FIG.19. Percent (%) live cells are plotted for cells harvested from mice untreated with CCl4(PBS control), and for cells harvested from mice that were treated with CCl4 to elicit liver injury and also administered either PBS, Cas9 payloaded ARMMs targeting NLRP3, or MCC950. These results demonstrate that treatment with Cas9 payloaded ARMMs targeting NLRP3 increases the number of live liver cells in the context of liver injury. TUNEL staining of mouse liver tissue sections For quantification of apoptotic cells via TUNEL assay, paraffin embedded cross sections from the left lateral lobe were processed using one-step TUNEL apoptosis kit (Elabscience E-CK-A322) according to manufacturer’s instructions (Elabscience, Houston, TX). Images from five regions (upper left, upper right, lower left, lower right, and center) were taken from two sections per mouse on an EXC-500 microscope (Accu-scope, Commack, NY) fitted with a DHYANA CMOS camera for fluorescent imaging (TUCSEN, Fujian, China) and recorded using Mosaic imaging software (Tucsen, version 1.6). TUNEL-stained images were thresholded in ImageJ software and the average percent thresholded area from the five regions was recorded as percentage TUNEL positive area. The average percentage of TUNEL positive areas from all regions and sections were calculated and reported for each individual mouse. Results from these TUNEL assays are shown in FIG.20. % area of TUNEL+ in liver sections is plotted for mice untreated with CCl4 (PBS control), and for cells harvested from mice that were treated with CCl4 to elicit liver injury and also administered either PBS, Cas9 payloaded ARMMs targeting NLRP3. These results demonstrate that treatment with Cas9 payloaded ARMMs targeting NLRP3 decreases apoptosis of liver cells in the context of liver injury. Attorney Docket No.54926-0014WO1 Example 6: High efficiency Intravenous Delivery of mCherry-payloaded ARMMs to Cynomolgus Monkey CD163+ Liver Non-parenchymal Cells Efficient ARMM biodistribution and Nlrp3 editing was observed in mouse Kupffer cells (FIG.18). Delivery of mCherry-payloaded ARMMs was evaluated in vivo by intravenous administration to cynomolgus monkeys. A single dose of 1x1013ARMMs.mCherry.P was delivered intravenously to cynomolgus monkeys. Delivery of mCherry is represented by native fluorescence observed with the target cells. Two hours after ARMMs.mCherry.P administration, livers were harvested and mCherry signal assessed in CD45+ CD163++ cells, commonly accepted as Kupffer cells. Kupffer cells (identified as CD45+CD163++), isolated from cynomolgus monkeys revealed robust mCherry signal in ARMMs.mCherry.P-treated monkeys as determined by flow cytometry (FIG.21A, right panel) in comparison to PBS-treated control animals (FIG.21A, left panel), with ~80-95% of flow-gated isolated Kupffer cells displaying mCherry signal from the 5 collected liver sections (FIG.21B). Cynomolgus dosing and tissue collection Cynomolgus monkeys aged 3-5 years, ~3kg, female, naïve were dosed intravenously with 1.5 mL of solution containing 1E13 ARMMs particles or Phosphate Buffered Saline (PBS). Briefly, monkeys were trained to participate in successful administration of intravenous injections. Intravenous administration was given with 5-minute flow rate for injection of 1.5 mL of test article. Monkeys were monitored for several minutes following administration. Twenty-four hours post- injection, monkeys were euthanized and livers were collected for downstream processing. Isolation of cynomolgus liver tissue for flow cytometry analysis Approximately 1-2 cm3liver cubes were isolated from various regions were placed in a 50mL conical tubes containing 20 mL DMEM+5% PBS+Pen / Strep and transported on ice. Livers cubes were carefully cut into small pieces using a scalpel in order to facilitate tissue digestion. Digestion media consisted of DMEM (with GLUTAMAX, Thermo Fisher 11965118) to a gentleMACs C tube (Miltenyi Biotec 130-093-237) and 200uL of enzyme D, 100uL of enzyme R, and 20uL of enzyme A (stored at -20) from Liver Dissociation kit, Miltenyi Bio (130-105-807) (Miltenyi Biotec, Charlestown, MA). Transferred the liver pieces to the gentleMACs C tube Attorney Docket No.54926-0014WO1 containing the liver digestion mixture and chose program 37_m_LIDK. The digested liver cell slurry was placed on a 70um cell strainer on a new 50mL conical tube. The strainer was pre-wetted with 5mL of DMEM. The slurry was washed gently with 5mL of additional DMEM and placed on the filter. The liver cell suspension was centrifuged at 300xg for 10 minutes at 4°C. The supernatant was discarded and the pellet was resuspended in 6.2 mL cold PBS then added 1.8 mL of cold debris remove solution (Miltenyi 130-109-398) to the solution and pipetted gently. The tubes were inverted about ten (10) times to set the walls. 4 mL of ice cold PBS was gently laid on top of the debris removal layer. The tubes were then placed in a centrifuge and spun at 3000xg 4°C for 10 minutes. The top 2 layers were aspirated off, and the tubes filled to 15 mL with cold PBS. The tubes were centrifuged at 1000xg for 10 minutes at 4°C. Cells pellets were resuspended in RBC lysis buffer and incubated on ice for 5 minutes. The tubes were centrifuged again at 400xg for 5 minutes at 4°C. Cell pellets were resuspended in PBS for single cell viable non-parenchymal cell suspensions suitable for further downstream applications. Approximately 1.0x105to 5.0x105cells were used for flow cytometry staining. Prior to antibody staining, live / dead fixable near IR (ThermoFisher L10119) staining was carried out according to manufacturer’s instructions. CD163+ liver non- parenchymal cells, commonly accepted in the field as Kupffer cells (REF), were identified as CD45+ CD163+. The following antibodies were used at a 1:100 dilution in Flow Cytometry Staining Buffer (eBiosciences #00-4222-26): CD45-FITC (BD Biosciences 557803) and CD163-APC (BioLegend 333610). mCherry intensity in the CD45+ CD163+ population was evaluated by native fluorescence. mCherry positive cells were gated based on an individual cynomolgus monkey administered with PBS in place of ARMMs as a negative control. Flow cytometry was performed on an Attune NxT flow cytometer, and data analysis performed on FCS Express (version 7). Example 7: High Efficiency In Vivo Nlrp3 Editing of ARMMs in cynomolgus to knock out Nlrp3 protein expression (FIG.22). Different guide RNAs were designed to target the cynomolgus NLRP3 gene (provided in Table 7 below) and the editing efficiency was tested by transiently transfecting ARRDC1-Cas9 and gRNA into Attorney Docket No.54926-0014WO1 monkey COS7 cells. gRNAs 6 (comprising spacer sequence SEQ ID NO: 97), 10 (comprising spacer sequence SEQ ID NO: 100), 11 (comprising spacer sequence SEQ ID NO: 101), 16 (comprising spacer sequence SEQ ID NO: 106), and 22 (comprising spacer sequence SEQ ID NO: 112) indicated potential further evaluation (FIG.22A). ARMMs payloaded with Cas9 and gRNA 6, 10, 11, 16, and 22 were additionally evaluated for genomic editing efficiency in COS7 cells at 1x106ARMMs / cell and 5x106ARMMs / cell (FIG.22B) and purified cynomolgus monocytes at 1x106ARMMs / cell and 5x106ARMMs / cell (FIG.22C). NHP #6 gRNA (comprising spacer sequence SEQ ID NO: 97) was chosen for further evaluation of cynomolgus NLRP3 genomic editing in studies. Table 7. Cynomolgus NLRP3 targeting gRNA sequences SEQ ID NO sequence Name 92AA A T AANlrp3 NHP #101234 567 8 9 0 1 2 3 4 Attorney Docket No.54926-0014WO1 As efficient ARMM.mCherry.P biodistribution was observed in treated cynomolgus monkeys (FIG.21) and successful gRNAs were identified to create indels in the cynomolgus NLRP3 gene locus (FIGs.22A-22C), NLPR3 editing with Cas9 and gRNA payloaded ARMMs targeting cynomolgus NLRP3 (Nlrp3_NHP #6 comprising spacer sequence SEQ ID NO: 97) were evaluated in vivo using intravenous administration to cynomolgus monkey (study schematized in FIG.23A). Animals were dosed intravenously with 1.5 mL of solution containing 1x1013ARMMs particles or Phosphate Buffered Saline (PBS).96 hours after ARMMs administration, livers were harvested and ~20% genomic editing efficiency of cynomolgus NLRP3 was observed from total liver tissue among 5 collected liver sections (FIG 23B). COS7 transfection and ARMM treatment for genomic editing assessment COS7 cells were transiently transfected with DNA encoding for Cas9 and gRNAs comprising spacer sequences SEQ ID NOs 92-114 as described in Table 7. Alternatively, COS7 cells or cynomolgus monocytes were treated with 1x106or 5x106ARMMs per cell of ARMMs payloaded with Cas9 and the gRNAs comprising spacer sequences SEQ ID NOs 92-114 as described in Table 7. Ninety-six hours post- injection, cells were assessed for genomic editing. gDNA was extracted using the DNeasy 96 Blood & Tissue Kit (Qiagen, 69581) following the manufacturer’s instructions. Targeted PCR was performed to amplify the genomic regions harboring the genome editing sites.5 µL of gDNA solution was used as template in the 50 µL PCR reaction using Q5 High-Fidelity 2X Master Mix (NEB, M0492) with the manufacturer’s protocols. PCR products were confirmed on E-gels and purified using the QIAquick 96 PCR Purification Kit (Qiagen, 28181).1-5 µL of the eluted PCR products were submitted for Sanger sequencing to have an initial evaluation of editing before the rest of PCR products were submitted for Amplicon deep sequencing. Results for percent (%) indel formation for gRNAs comprising spacer sequences SEQ ID NOs 92-101, 103, 105-107, 110, and 112-114 are shown in FIG.22A. Results for percent (%) indel formation for gRNAs comprising spacer sequences SEQ ID NOs 92-101, 103, 105-107, 110, and 112-114 are shown in FIG.22A. Results for administration of 1x106or 5x106ARMMs per cell of ARMMs payloaded with Cas9 and the gRNAs comprising spacer sequences SEQ ID NOs 97, 100, 101, 106, and 112 are shown in FIG.22B. Attorney Docket No.54926-0014WO1 Cynomolgus dosing and tissue collection for genomic editing assessment Cynomolgus monkeys aged 3-5 years, ~3kg, female, naïve were dosed intravenously with 1.5 mL of solution containing 1x1013ARMMs particles payloaded with Cas9 and gRNA comprising spacer sequence SEQ ID NO: 97, or Phosphate Buffered Saline (PBS) as a control. Briefly, monkeys were trained to participate in successful administration of intravenous injections. Intravenous administration given with 5-minute flow rate for injection of 1.5 mL of test article. Monkeys were monitored for several minutes following administration. Ninety-six hours post- injection, monkeys were euthanized and livers were collected for assessment of genomic editing. gDNA was extracted using the DNeasy 96 Blood & Tissue Kit (Qiagen, 69581) and following the manufacturer’s instructions. Targeted PCR was performed to amplify the genomic regions harboring the genome editing sites.5 µL of gDNA solution was used as template in the 50 µL PCR reaction using Q5 High- Fidelity 2X Master Mix (NEB, M0492) with the manufacturer’s protocols. PCR products were confirmed on E-gels and purified using the QIAquick 96 PCR Purification Kit (Qiagen, 28181).1-5 µL of the eluted PCR products were submitted for Sanger sequencing to have an initial evaluation of editing before the rest of PCR products were submitted for Amplicon deep sequencing. As shown in the plot of FIG. 23B, ~20% genomic editing efficiency of cynomolgus NLRP3 was observed from total liver tissue among 5 collected liver sections in this experiment. These results demonstrate effective editing of the NLRP3 gene in vivo after intravenous delivery of ARMMs particles payloaded with Cas9 and gRNA targeting the NLRP3 gene in a Cynomolgus animal model.

[0002] Attorney Docket No.54926-0014WO1 SEQUENCES SEQ ID NO: 35 (PSAP motif) PSAP SEQ ID NO: 36 (GFP) MSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTFSYGVQ CFSRYPDHMKQHDFFKSAMPEGYVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNILG HKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIEDGSVQLADHYQQNTPIGDGPVLLPDNHYLSTQSAL SKDPNEKRDHMVLLEFVTAAGITHGMDELYK SEQ ID NO: 37 (WT spCas9) MDKKYSIGLDIGTNSVGWAVITDDYKVPSKKFKVLGNTDRHSIKKNLIGALLFGSGETAEATRLKRTAR RRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIYHL RKKLADSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQIYNQLFEENPINASRVD AKAILSARLSKSRRLENLIAQLPGEKRNGLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLD NLLAQIGDQYADLFLAAKNLSDAILLSDILRVNSEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPE KYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVD KGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLL FKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGAYHDLLKIIKDKDFLDNEENEDILEDIVL TLTLFEDRGMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFAN RNFMQLIHDDSLTFKEDIQKAQVSGQGHSLHEQIANLAGSPAIKKGILQTVKIVDELVKVMGHKPENIV IEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELD INRLSDYDVDHIVPQSFIKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFR KDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKY FFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGF SKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSF EKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYE KLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHL FTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGD SEQ ID NO: 38 MDKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATRLKRTAR RRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIYHL RKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENPINASGVD AKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLD NLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPE KYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI Attorney Docket No.54926-0014WO1 HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVD KGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLL FKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVL TLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFAN RNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENI VIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQEL DINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKF DNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDF RKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAK YFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGG FSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSS FEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHY EKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIH LFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGD SEQ ID NO: 39 (Human ARRDC1) >gi|22748653|ref|NP_689498.1| arrestin domain-containing protein 1 [Homo sapiens] MGRVQLFEISLSHGRVVYSPGEPLAGTVRVRLGAPLPFRAIRVTCIGSCGVSNKANDTAWVVEEGYFNS SLSLADKGSLPAGEHSFPFQFLLPATAPTSFEGPFGKIVHQVRAAIHTPRFSKDHKCSLVFYILSPLNL NSIPDIEQPNVASATKKFSYKLVKTGSVVLTASTDLRGYVVGQALQLHADVENQSGKDTSPVVASLLQKVSYKAKRWIHDVRTIAEVEGAGVKAWRRAQWHEQILVPALPQSALPGCSLIHIDYYLQVSLKAPEATVTLPVFIGNIAVNHAPVSPRPGLGLPPGAPPLVVPSAPPQEEAEAEAAAGGPHFLDPVFLSTKSHSQRQPL SEQ ID NO: 40 (Mouse ARRDC1, isoform a) >gi|244798004|ref|NP_001155957.1| arrestin domain-containing protein 1 isoform a [Mus musculus] MGRVQLFEIRLSQGRVVYGPGEPLAGTVHLRLGAPLPFRAIRVTCMGSCGVSTKANDGAWVVEESYFNS SLSLADKGSLPAGEHNFPFQFLLPATAPTSFEGPFGKIVHQVRASIDTPRFSKDHKCSLVFYILSPLNL NSIPDIEQPNVASTTKKFSYKLVKTGNVVLTASTDLRGYVVGQVLRLQADIENQSGKDTSPVVASLLQK VSYKAKRWIYDVRTIAEVEGTGVKAWRRAQWQEQILVPALPQSALPGCSLIHIDYYLQVSMKAPEATVTLPLFVGNIAVNQTPLSPCPGRESSPGTLSLVVPSAPPQEEAEAVASGPHFSDPVSLSTKSHSQQQPLSAPLGSVSVTTTEPWVQVGSPARHSLHPPLCISIGATVPYFAEGSAGPVPTTSALILPPEYSSWGYPYEAP PSYEQSCGAAGTDLGLIPGS SEQ ID NO: 41 (Mouse ARRDC1, isoform b) >gi|244798112|ref|NP_848495.2| arrestin domain-containing protein 1 isoform b [Mus musculus]MGRVQLFEIRLSQGRVVYGPGEPLAGTVHLRLGAPLPFRAIRVTCMGSCGVSTKANDGAWVVEESYFNSSLSLADKGSLPAGEHNFPFQFLLPATAPTSFEGPFGKIVHQVRASIDTPRFSKDHKCSLVFYILSPLNL NSIPDIEQPNVASTTKKFSYKLVKTGNVVLTASTDLRGYVVGQVLRLQADIENQSGKDTSPVVASLLQV SYKAKRWIYDVRTIAEVEGTGVKAWRRAQWQEQILVPALPQSALPGCSLIHIDYYLQVSMKAPEATVTL Attorney Docket No.54926-0014WO1 PLFVGNIAVNQTPLSPCPGRESSPGTLSLVVPSAPPQEEAEAVASGPHFSDPVSLSTKSHSQQQPLSAP LGSVSVTTTEPWVQVGSPARHSLHPPLCISIGATVPYFAEGSAGPVPTTSALILPPEYSSWGYPYEAPP SYEQSCGAAGTDLGLIPGS SEQ ID NO: 42 (Human TSG101) >gi|5454140|ref|NP_006283.1| tumor susceptibility gene 101 protein [Homo sapiens]MAVSESQLKKMVSKYKYRDLTVRETVNVITLYKDLKPVLDSYVFNDGSSRELMNLTGTIPVPYRGNTYN IPICLWLLDTYPYNPPICFVKPTSSMTIKTGKHVDANGKIYLPYLHEWKHPQSDLLGLIQVMIVVFGDE PPVFSRPISASYPPYQATGPPNTSYMPGMPGGISPYPSGYPPNPSGYPGCPYPPGGPYPATTSSQYPSQ PPVTTVGPSRDGTISEDTIRASLISAVSDKLRWRMKEEMDRAQAELNALKRTEEDLKKGHQKLEEMVTR LDQEVAEVDKNIELLKKKDEELSSALEKMENQSENNDIDEVIIPTAPLYKQILNLYAEENAIEDTIFYL GEALRRGVIDLDVFLKHVRLLSRKQFQLRALMQKARKTAGLSDLY SEQ ID NO: 43 (Mouse TSG101) >gi|11230780|ref|NP_068684.1| tumor susceptibility gene 101 protein [Mus musculus] MAVSESQLKKMMSKYKYRDLTVRQTVNVIAMYKDLKPVLDSYVFNDGSSRELVNLTGTIPVRYRGNIYNIPICLWLLDTYPYNPPICFVKPTSSMTIKTGKHVDANGKIYLPYLHDWKHPRSELLELIQIMIVIFGEEPPVFSRPTVSASYPPYTATGPPNTSYMPGMPSGISAYPSGYPPNPSGYPGCPYPPAGPYPATTSSQYPS QPPVTTVGPSRDGTISEDTIRASLISAVSDKLRWRMKEEMDGAQAELNALKRTEEDLKKGHQKLEEMVT RLDQEVAEVDKNIELLKKKDEELSSALEKMENQSENNDIDEVIIPTAPLYKQILNLYAEENAIEDTIFY LGEALRRGVIDLDVFLKHVRLLSRKQFQLRALMQKARKTAGLSDLYSEQ ID NO: 44 (Rat TSG101)>gi|48374087|ref|NP_853659.2| tumor susceptibility gene 101 protein [Rattus norvegicus] MAVSESQLKKMMSKYKYRDLTVRQTVNVIAMYKDLKPVLDSYVFNDGSSRELVNLTGTIPVRYRGNIYN IPICLWLLDTYPYNPPICFVKPTSSMTIKTGKHVDANGKIYLPYLHDWKHPRSELLELIQIMIVIFGEE PPVFSRPTVSASYPPYTAAGPPNTSYLPSMPSGISAYPSGYPPNPSGYPGCPYPPAGPYPATTSSQYPS QPPVTTAGPSRDGTISEDTIRASLISAVSDKLRWRMKEEMDGAQAELNALKRTEEDLKKGHQKLEEMVT RLDQEVAEVDKNIELLKKKDEELSSALEKMENQSENNDIDEVIIPTAPLYKQILNLYAEENAIEDTIFY LGEALRRGVIDLDVFLKHVRLLSRKQFQLRALMQKARKTAGLSDLY SEQ ID NO: 45 (Human WWP1 amino acid sequence (uniprot.org / uniprot / Q9H0M0). The four underlined WW domains correspond to amino acids 349 – 382 (WW1), 381 – 414 (WW2), 456 – 489 (WW3), and 496 – 529 (WW4). MATASPRSDTSNNHSGRLQLQVTVSSAKLKRKKNWFGTAIYTEVVVDGEITKTAKSSSSSNPKWDEQLT VNVTPQTTLEFQVWSHRTLKADALLGKATIDLKQALLIHNRKLERVKEQLKLSLENKNGIAQTGELTVV LDGLVIEQENITNCSSSPTIEIQENGDALHENGEPSARTTARLAVEGTNGIDNHVPTSTLVQNSCCSYV VNGDNTPSSPSQVAARPKNTPAPKPLASEPADDTVNGESSSFAPTDNASVTGTPVVSEENALSPNCTST TVEDPPVQEILTSSENNECIPSTSAELESEARSILEPDTSNSRSSSAFEAAKSRQPDGCMDPVRQQSGN ANTETLPSGWEQRKDPHGRTYYVDHNTRTTTWERPQPLPPGWERRVDDRRRVYYVDHNTRTTTWQRPTM ESVRNFEQWQSQRNQLQGAMQQFNQRYLYSASMLAAENDPYGPLPPGWEKRVDSTDRVYFVNHNTKTTQ Attorney Docket No.54926-0014WO1 WEDPRTQGLQNEEPLPEGWEIRYTREGVRYFVDHNTRTTTFKDPRNGKSSVTKGGPQIAYERGFRWKLA HFRYLCQSNALPSHVKINVSRQTLFEDSFQQIMALKPYDLRRRLYVIFRGEEGLDYGGLAREWFFLLSH EVLNPMYCLFEYAGKNNYCLQINPASTINPDHLSYFCFIGRFIAMALFHGKFIDTGFSLPFYKRMLSKK LTIKDLESIDTEFYNSLIWIRDNNIEECGLEMYFSVDMEILGKVTSHDLKLGGSNILVTEENKDEYIGL MTEWRFSRGVQEQTKAFLDGFNEVVPLQWLQYFDEKELEVMLCGMQEVDLADWQRNTVYRHYTRNSKQI IWFWQFVKETDNEVRMRLLQFVTGTCRLPLGGFAELMGSNGPQKFCIEKVGKDTWLPRSHTCFNRLDLP PYKSYEQLKEKLLFAIEETEGFGQE SEQ ID NO: 46 (WW1 (349-382))ETLPSGWEQRKDPHGRTYYVDHNTRTTTWERPQPSEQ ID NO: 47 (WW2 (381-414)) QPLPPGWERRVDDRRRVYYVDHNTRTTTWQRPTM SEQ ID NO: 48 (WW3 (456-489)) ENDPYGPLPPGWEKRVDSTDRVYFVNHNTKTTQWEDPRT SEQ ID NO: 49 (WW4 (496-529)) EPLPEGWEIRYTREGVRYFVDHNTRTTTFKDPRN SEQ ID NO: 50 (Human WWP2 amino acid sequence (uniprot.org / uniprot / O00308). The four underlined WW domains correspond to amino acids 300 – 333 (WW1), 330 – 363 (WW2), 405 – 437 (WW3), and 444 – 547 (WW4)) MASASSSRAGVALPFEKSQLTLKVVSAKPKVHNRQPRINSYVEVAVDGLPSETKKTGKRIGSSELLWNE IIILNVTAQSHLDLKVWSCHTLRNELLGTASVNLSNVLKNNGGKMENMQLTLNLQTENKGSVVSGGELT IFLDGPTVDLGNVPNGSALTDGSQLPSRDSSGTAVAPENRHQPPSTNCFGGRSRTHRHSGASARTTPAT GEQSPGARSRHRQPVKNSGHSGLANGTVNDEPTTATDPEEPSVVGVTSPPAAPLSVTPNPNTTSLPAPA TPAEGEEPSTSGTQQLPAAAQAPDALPAGWEQRELPNGRVYYVDHNTKTTTWERPLPPGWEKRTDPRGR FYYVDHNTRTTTWQRPTAEYVRNYEQWQSQRNQLQGAMQHFSQRFLYQSSSASTDHDPLGPLPPGWEKR QDNGRVYYVNHNTRTTQWEDPRTQGMIQEPALPPGWEMKYTSEGVRYFVDHNTRTTTFKDPRPGFESGT KQGSPGAYDRSFRWKYHQFRFLCHSNALPSHVKISVSRQTLFEDSFQQIMNMKPYDLRRRLYIIMRGEE GLDYGGIAREWFFLLSHEVLNPMYCLFEYAGKNNYCLQINPASSINPDHLTYFRFIGRFIAMALYHGKF IDTGFTLPFYKRMLNKRPTLKDLESIDPEFYNSIVWIKENNLEECGLELYFIQDMEILGKVTTHELKEG GESIRVTEENKEEYIMLLTDWRFTRGVEEQTKAFLDGFNEVAPLEWLRYFDEKELELMLCGMQEIDMSD WQKSTIYRHYTKNSKQIQWFWQVVKEMDNEKRIRLLQFVTGTCRLPVGGFAELIGSNGPQKFCIDKVGK ETWLPRSHTCFNRLDLPPYKSYEQLREKLLYAIEETEGFGQE SEQ ID NO: 51 (WW1 (300-333)) DALPAGWEQRELPNGRVYYVDHNTKTTTWERPLP SEQ ID NO: 52 (WW2 (330-363)) PLPPGWEKRT DPRGRFYYVDHNTRTTTWQRPTA Attorney Docket No.54926-0014WO1 SEQ ID NO: 53 (WW3 (405-437)) HDPLGPLPPGWEKRQDNGRVYYVNHNTRTTQWEDPRT SEQ ID NO: 54 (WW4 (444-477)) PALPPGWEMKYTSEGVRYFVDHNTRTTTFKDPRP SEQ ID NO: 55 (Human Nedd4-1 amino acid sequence (uniprot.org / uniprot / P46934). The four underlined WW domains correspond to amino acids 610 – 643 (WW1), 767 – 800 (WW2), 840 – 873 (WW3), and 892 – 925 (WW4)). MAQSLRLHFAARRSNTYPLSETSGDDLDSHVHMCFKRPTRISTSNVVQMKLTPRQTALAPLIKENVQSQ ERSSVPSSENVNKKSSCLQISLQPTRYSGYLQSSNVLADSDDASFTCILKDGIYSSAVVDNELNAVNDG HLVSSPAICSGSLSNFSTSDNGSYSSNGSDFGSCASITSGGSYTNSVISDSSSYTFPPSDDTFLGGNLP SDSTSNRSVPNRNTTPCEIFSRSTSTDPFVQDDLEHGLEIMKLPVSRNTKIPLKRYSSLVIFPRSPSTT RPTSPTSLCTLLSKGSYQTSHQFIISPSEIAHNEDGTSAKGFLSTAVNGLRLSKTICTPGEVRDIRPLH RKGSLQKKIVLSNNTPRQTVCEKSSEGYSCVSVHFTQRKAATLDCETTNGDCKPEMSEIKLNSDSEYIK LMHRTSACLPSSQNVDCQININGELERPHSQMNKNHGILRRSISLGGAYPNISCLSSLKHNCSKGGPSQ LLIKFASGNEGKVDNLSRDSNRDCTNELSNSCKTRDDFLGQVDVPLYPLPTENPRLERPYTFKDFVLHP RSHKSRVKGYLRLKMTYLPKTSGSEDDNAEQAEELEPGWVVLDQPDAACHLQQQQEPSPLPPGWEERQD ILGRTYYVNHESRRTQWKRPTPQDNLTDAENGNIQLQAQRAFTTRRQISEETESVDNRESSENWEIIRE DEATMYSNQAFPSPPPSSNLDVPTHLAEELNARLTIFGNSAVSQPASSSNHSSRRGSLQAYTFEEQPTL PVLLPTSSGLPPGWEEKQDERGRSYYVDHNSRTTTWTKPTVQATVETSQLTSSQSSAGPQSQASTSDSG QQVTQPSEIEQGFLPKGWEVRHAPNGRPFFIDHNTKTTTWEDPRLKIPAHLRGKTSLDTSNDLGPLPPG WEERTHTDGRIFYINHNIKRTQWEDPRLENVAITGPAVPYSRDYKRKYEFFRRKLKKQNDIPNKFEMKL RRATVLEDSYRRIMGVKRADFLKARLWIEFDGEKGLDYGGVAREWFFLISKEMFNPYYGLFEYSATDNY TLQINPNSGLCNEDHLSYFKFIGRVAGMAVYHGKLLDGFFIRPFYKMMLHKPITLHDMESVDSEYYNSL RWILENDPTELDLRFIIDEELFGQTHQHELKNGGSEIVVTNKNKKEYIYLVIQWRFVNRIQKQMAAFKE GFFELIPQDLIKIFDENELELLMCGLGDVDVNDWREHTKYKNGYSANHQVIQWFWKAVLMMDSEKRIRL LQFVTGTSRVPMNGFAELYGSNGPQSFTVEQWGTPEKLPRAHTCFNRLDLPPYESFEELWDKLQMAIEN TQGFDGVD SEQ ID NO: 56 (WW1(610-643)): SPLPPGWEERQDILGRTYYVNHESRRTQWKRPTP SEQ ID NO: 57 (WW2 (767-800)): SGLPPGWEEKQDERGRSYYVDHNSRTTTWTKPTV SEQ ID NO: 58 (WW3 (840-873)): GFLPKGWEVRHAPNGRPFFIDHNTKTTTWEDPRL SEQ ID NO: 59 (WW4 (892-925)): GPLPPGWEERTHTDGRIFYINHNIKRTQWEDPRL Attorney Docket No.54926-0014WO1 SEQ ID NO: 60 (Human Nedd4-2 amino acid sequence (>gi|21361472|ref|NP_056092.2| E3 ubiquitin- protein ligase NEDD4-like isoform 3 [Homo sapiens]). The four underlined WW domains correspond to amino acids 198 – 224 (WW1), 368 – 396 (WW2), 480 – 510 (WW3), and 531 – 561 (WW4)). MATGLGEPVYGLSEDEGESRILRVKVVSGIDLAKKDIFGASDPYVKLSLYVADENRELALVQTKTIKKT LNPKWNEEFYFRVNPSNHRLLFEVFDENRLTRDDFLGQVDVPLSHLPTEDPTMERPYTFKDFLLRPRSH KSRVKGFLRLKMAYMPKNGGQDEENSDQRDDMEHGWEVVDSNDSASQHQEELPPPPLPPGWEEKVDNLG RTYYVNHNNRTTQWHRPSLMDVSSESDNNIRQINQEAAHRRFRSRRHISEDLEPEPSEGGDVPEPWETI SEEVNIAGDSLGLALPPPPASPGSRTSPQELSEELSRRLQITPDSNGEQFSSLIQREPSSRLRSCSVTD AVAEQGHLPPPSVAYVHTTPGLPSGWEERKDAKGRTYYVNHNNRTTTWTRPIMQLAEDGASGSATNSNN HLIEPQIRRPRSLSSPTVTLSAPLEGAKDSPVRRAVKDTLSNPQSPQPSPYNSPKPQHKVTQSFLPPGW EMRIAPNGRPFFIDHNTKTTTWEDPRLKFPVHMRSKTSLNPNDLGPLPPGWEERIHLDGRTFYIDHNSK ITQWEDPRLQNPAITGPAVPYSREFKQKYDYFRKKLKKPADIPNRFEMKLHRNNIFEESYRRIMSVKRP DVLKARLWIEFESEKGLDYGGVAREWFFLLSKEMFNPYYGLFEYSATDNYTLQINPNSGLCNEDHLSYF TFIGRVAGLAVFHGKLLDGFFIRPFYKMMLGKQITLNDMESVDSEYYNSLKWILENDPTELDLMFCIDE ENFGQTYQVDLKPNGSEIMVTNENKREYIDLVIQWRFVNRVQKQMNAFLEGFTELLPIDLIKIFDENEL ELLMCGLGDVDVNDWRQHSIYKNGYCPNHPVIQWFWKAVLLMDAEKRIRLLQFVTGTSRVPMNGFAELY GSNGPQLFTIEQWGSPEKLPRAHTCFNRLDLPPYETFEDLREKLLMAVENAQGFEGVD SEQ ID NO: 61 (WW1(198 – 224)): GWEEKVDNLGRTYYVNHNNRTTQWHRP SEQ ID NO: 62 (WW2 (368 – 396)): PSGWEERKDAKGRTYYVNHNNRTTTWTRP SEQ ID NO: 63 (WW3 (480 – 510)): PPGWEMRIAPNGRPFFIDHNTKTTTWEDPRL SEQ ID NO: 64 (WW4 (531 – 561)): PPGWEERIHLDGRTFYIDHNSKITQWEDPRL SEQ ID NO: 65 (Human Smurf1 amino acid sequence (uniprot.org / uniprot / Q9HCE7). The two underlined WW domains correspond to amino acids 234 – 267 (WW1) and 306 – 339 (WW2).) MSNPGTRRNGSSIKIRLTVLCAKNLAKKDFFRLPDPFAKIVVDGSGQCHSTDTVKNTLDPKWNQHYDLY VGKTDSITISVWNHKKIHKKQGAGFLGCVRLLSNAISRLKDTGYQRLDLCKLNPSDTDAVRGQIVVSLQ TRDRIGTGGSVDCRGLLENEGTVYEDSGPGRPLSCFMEEPAPYTDSTGAAAGGGNCRFVESPSQDQRLQ AQRLRNPDVRGSLQTPQNRPHGHQSPELPEGYEQRTTVQGQVYFLHTQTGVSTWHDPRIPSPSGTIPGG DAAFLYEFLLQGHTSEPRDLNSVNCDELGPLPPGWEVRSTVSGRIYFVDHNNRTTQFTDPRLHHIMNHQ CQLKEPSQPLPLPSEGSLEDEELPAQRYERDLVQKLKVLRHELSLQQPQAGHCRIEVSREEIFEESYRQ IMKMRPKDLKKRLMVKFRGEEGLDYGGVAREWLYLLCHEMLNPYYGLFQYSTDNIYMLQINPDSSINPD HLSYFHFVGRIMGLAVFHGHYINGGFTVPFYKQLLGKPIQLSDLESVDPELHKSLVWILENDITPVLDH TFCVEHNAFGRILQHELKPNGRNVPVTEENKKEYVRLYVNWRFMRGIEAQFLALQKGFNELIPQHLLKP Attorney Docket No.54926-0014WO1 FDQKELELIIGGLDKIDLNDWKSNTRLKHCVADSNIVRWFWQAVETFDEERRARLLQFVTGSTRVPLQG FKALQGSTGAAGPRLFTIHLIDANTDNLPKAHTCFNRIDIPPYESYEKLYEKLLTAVEETCGFAVE SEQ ID NO: 66 (WW1 (234-267)): PELPEGYEQRTTVQGQVYFLHTQTGVSTWHDPRI SEQ ID NO: 67 (WW2 (306-339)): GPLPPGWEVRSTVSGRIYFVDHNNRTTQFTDPRL SEQ ID NO: 68 (Human Smurf2 amino acid sequence (uniprot.org / uniprot / Q9HAU4). The three underlined WW domains correspond to amino acids 157 – 190 (WW1), 251 – 284 (WW2), and 297 – 330 (WW3)). MSNPGGRRNGPVKLRLTVLCAKNLVKKDFFRLPDPFAKVVVDGSGQCHSTDTVKNTLDPKWNQHYDLYI GKSDSVTISVWNHKKIHKKQGAGFLGCVRLLSNAINRLKDTGYQRLDLCKLGPNDNDTVRGQIVVSLQS RDRIGTGGQVVDCSRLFDNDLPDGWEERRTASGRIQYLNHITRTTQWERPTRPASEYSSPGRPLSCFVD ENTPISGTNGATCGQSSDPRLAERRVRSQRHRNYMSRTHLHTPPDLPEGYEQRTTQQGQVYFLHTQTGV STWHDPRVPRDLSNINCEELGPLPPGWEIRNTATGRVYFVDHNNRTTQFTDPRLSANLHLVLNRQNQLK DQQQQQVVSLCPDDTECLTVPRYKRDLVQKLKILRQELSQQQPQAGHCRIEVSREEIFEESYRQVMKMR PKDLWKRLMIKFRGEEGLDYGGVAREWLYLLSHEMLNPYYGLFQYSRDDIYTLQINPDSAVNPEHLSYF HFVGRIMGMAVFHGHYIDGGFTLPFYKQLLGKSITLDDMELVDPDLHNSLVWILENDITGVLDHTFCVE HNAYGEIIQHELKPNGKSIPVNEENKKEYVRLYVNWRFLRGIEAQFLALQKGFNEVIPQHLLKTFDEKE LELIICGLGKIDVNDWKVNTRLKHCTPDSNIVKWFWKAVEFFDEERRARLLQFVTGSSRVPLQGFKALQ GAAGPRLFTIHQIDACTNNLPKAHTCFNRIDIPPYESYEKLYEKLLTAIEETCGFAVE SEQ ID NO: 69 (WW1 (157-190)): NDLPDGWEERRTASGRIQYLNHITRTTQWERPTR SEQ ID NO: 70 (WW2 (251-284)): PDLPEGYEQRTTQQGQVYFLHTQTGVSTWHDPRV SEQ ID NO: 71 (WW3 (297-330)): GPLPPGWEIRNTATGRVYFVDHNNRTTQFTDPRL SEQ ID NO: 72 (Human ITCH amino acid sequence (uniprot.org / uniprot / Q96J02). The four underlined WW domains correspond to amino acids 326 – 359 (WW1), 358 – 391 (WW2), 438 – 471 (WW3), and 478 – 511 (WW4).) MSDSGSQLGSMGSLTMKSQLQITVISAKLKENKKNWFGPSPYVEVTVDGQSKKTEKCNNTNSPKWKQPL TVIVTPVSKLHFRVWSHQTLKSDVLLGTAALDIYETLKSNNMKLEEVVVTLQLGGDKEPTETIGDLSICLDGLQLESEVVTNGETTCSENGVSLCLPRLECNSAISAHCNLCLPGLSDSPISASRVAGFTGASQNDDGSRSKDETRVSTNGSDDPEDAGAGENRRVSGNNSPSLSNGGFKPSRPPRPSRPPPPTPRRPASVNGSPSA TSESDGSSTGSLPPTNTNTNTSEGATSGLIIPLTISGGSGPRPLNPVTQAPLPPGWEQRVDQHGRVYYV Attorney Docket No.54926-0014WO1 DHVEKRTTWDRPEPLPPGWERRVDNMGRIYYVDHFTRTTTWQRPTLESVRNYEQWQLQRSQLQGAMQQF NQRFIYGNQDLFATSQSKEFDPLGPLPPGWEKRTDSNGRVYFVNHNTRITQWEDPRSQGQLNEKPLPEG WEMRFTVDGIPYFVDHNRRTTTYIDPRTGKSALDNGPQIAYVRDFKAKVQYFRFWCQQLAMPQHIKITV TRKTLFEDSFQQIMSFSPQDLRRRLWVIFPGEEGLDYGGVAREWFFLLSHEVLNPMYCLFEYAGKDNYC LQINPASYINPDHLKYFRFIGRFIAMALFHGKFIDTGFSLPFYKRILNKPVGLKDLESIDPEFYNSLIW VKENNIEECDLEMYFSVDKEILGEIKSHDLKPNGGNILVTEENKEEYIRMVAEWRLSRGVEEQTQAFFE GFNEILPQQYLQYFDAKELEVLLCGMQEIDLNDWQRHAIYRHYARTSKQIMWFWQFVKEIDNEKRMRLL QFVTGTCRLPVGGFADLMGSNGPQKFCIEKVGKENWLPRSHTCFNRLDLPPYKSYEQLKEKLLFAIEET EGFGQE SEQ ID NO: 73 (ITCH WW1 (326-359)): APLPPGWEQRVDQHGRVYYVDHVEKRTTWDRPEP SEQ ID NO: 74 (ITCH WW2 (358-391)): EPLPPGWERRVDNMGRIYYVDHFTRTTTWQRPTL SEQ ID NO: 75 (ITCH WW3 (438-471)): GPLPPGWEKRTDSNGRVYFVNHNTRITQWEDPRS SEQ ID NO: 76 (ITCH WW4 (478-511)): KPLPEGWEMRFTVDGIPYFVDHNRRTTTYIDPRT SEQ ID NO: 77 (Human NEDL1 amino acid sequence (uniprot.org / uniprot / Q76N89). The two underlined WW domains correspond to amino acids 829 – 862 (WW1), and 1018 – 1051 (WW2)) MLLHLCSVKN LYQNRFLGLA AMASPSRNSQ SRRRCKEPLR YSYNPDQFHN MDLRGGPHDG VTIPRSTSDT DLVTSDSRST LMVSSSYYSI GHSQDLVIHW DIKEEVDAGD WIGMYLIDEV LSENFLDYKN RGVNGSHRGQ IIWKIDASSY FVEPETKICF KYYHGVSGAL RATTPSVTVK NSAAPIFKSI GADETVQGQG SRRLISFSLS DFQAMGLKKG MFFNPDPYLK ISIQPGKHSI FPALPHHGQE RRSKIIGNTV NPIWQAEQFS FVSLPTDVLE IEVKDKFAKS RPIIKRFLGK LSMPVQRLLE RHAIGDRVVS YTLGRRLPTD HVSGQLQFRF EITSSIHPDD EEISLSTEPE SAQIQDSPMN NLMESGSGEP RSEAPESSES WKPEQLGEGS VPDGPGNQSI ELSRPAEEAA VITEAGDQGM VSVGPEGAGE LLAQVQKDIQ PAPSAEELAE QLDLGEEASA LLLEDGEAPA STKEEPLEEE ATTQSRAGRE EEEKEQEEEG DVSTLEQGEG RLQLRASVKR KSRPCSLPVS ELETVIASAC GDPETPRTHY IRIHTLLHSM PSAQGGSAAE EEDGAEEEST LKDSSEKDGL SEVDTVAADP SALEEDREEP EGATPGTAHP GHSGGHFPSL ANGAAQDGDT HPSTGSESDS SPRQGGDHSC EGCDASCCSP SCYSSSCYST SCYSSSCYSA SCYSPSCYNG NRFASHTRFS SVDSAKISES TVFSSQDDEE EENSAFESVPDSMQSPELDP ESTNGAGPWQ DELAAPSGHV ERSPEGLESP VAGPSNRREGECPILHNSQP VSQLPSLRPE HHHYPTIDEP LPPNWEARID SHGRVFYVDH VNRTTTWQRP TAAATPDGMR RSGSIQQMEQ LNRRYQNIQR TIATERSEED Attorney Docket No.54926-0014WO1 SGSQSCEQAP AGGGGGGGSD SEAESSQSSL DLRREGSLSP VNSQKITLLL QSPAVKFITN PEFFTVLHAN YSAYRVFTSS TCLKHMILKV RRDARNFERY QHNRDLVNFI NMFADTRLEL PRGWEIKTDQ QGKSFFVDHN SRATTFIDPR IPLQNGRLPN HLTHRQHLQR LRSYSAGEAS EVSRNRGASL LARPGHSLVA AIRSQHQHES LPLAYNDKIV AFLRQPNIFE MLQERQPSLA RNHTLREKIH YIRTEGNHGL EKLSCDADLV ILLSLFEEEI MSYVPLQAAF HPGYSFSPRC SPCSSPQNSP GLQRASARAP SPYRRDFEAK LRNFYRKLEA KGFGQGPGKI KLIIRRDHLL EGTFNQVMAY SRKELQRNKL YVTFVGEEGL DYSGPSREFF FLLSQELFNP YYGLFEYSAN DTYTVQISPM SAFVENHLEW FRFSGRILGL ALIHQYLLDA FFTRPFYKAL LRLPCDLSDL EYLDEEFHQS LQWMKDNNIT DILDLTFTVN EEVFGQVTER ELKSGGANTQ VTEKNKKEYI ERMVKWRVER GVVQQTEALV RGFYEVVDSR LVSVFDAREL ELVIAGTAEI DLNDWRNNTE YRGGYHDGHL VIRWFWAAVE RFNNEQRLRL LQFVTGTSSV PYEGFAALRG SNGLRRFCIE KWGKITSLPR AHTCFNRLDL PPYPSYSMLY EKLLTAVEET STFGLE SEQ ID NO: 78 (WW1 (829-862)): PLPPNWEARIDSHGRVFYVDHVNRTTTWQRPTA SEQ ID NO: 79 (WW2 (1018-1051)): LELPRGWEIKTDQQGKSFFVDHNSRATTFIDPRI SEQ ID NO: 80 (Human NEDL2 amino acid sequence (uniprot.org / uniprot / Q9P2P5). The two underlined WW domains correspond to amino acids 807 – 840 (WW1) and 985 – 1018 (WW2). MASSAREHLLFVRRRNPQMRYTLSPENLQSLAAQSSMPENMTLQRANSDTDLVTSESRSSLTASMYEYT LGQAQNLIIFWDIKEEVDPSDWIGLYHIDENSPANFWDSKNRGVTGTQKGQIVWRIEPGPYFMEPEIKI CFKYYHGISGALRATTPCITVKNPAVMMGAEGMEGGASGNLHSRKLVSFTLSDLRAVGLKKGMFFNPDP YLKMSIQPGKKSSFPTCAHHGQERRSTIISNTTNPIWHREKYSFFALLTDVLEIEIKDKFAKSRPIIKR FLGKLTIPVQRLLERQAIGDQMLSYNLGRRLPADHVSGYLQFKVEVTSSVHEDASPEAVGTILGVNSVN GDLGSPSDDEDMPGSHHDSQVCSNGPVSEDSAADGTPKHSFRTSSTLEIDTEELTSTSSRTSPPRGRQD SLNDYLDAIEHNGHSRPGTATCSERSMGASPKLRSSFPTDTRLNAMLHIDSDEEDHEFQQDLGYPSSLE EEGGLIMFSRASRADDGSLTSQTKLEDNPVENEEASTHEAASFEDKPENLPELAESSLPAGPAPEEGEG GPEPQPSADQGSAELCGSQEVDQPTSGADTGTSDASGGSRRAVSETESLDQGSEPSQVSSETEPSDPAR TESVSEASTRPEGESDLECADSSCNESVTTQLSSVDTRCSSLESARFPETPAFSSQEEEDGACAAEPTS SGPAEGSQESVCTAGSLPVVQVPSGEDEGPGAESATVPDQEELGEVWQRRGSLEGAAAAAESPPQEEGS AGEAQGTCEGATAQEEGATGGSQANGHQPLRSLPSVRQDVSRYQRVDEALPPNWEARIDSHGRIFYVDH VNRTTTWQRPTAPPAPQVLQRSNSIQQMEQLNRRYQSIRRTMTNERPEENTNAIDGAGEEADFHQASAD FRRENILPHSTSRSRITLLLQSPPVKFLISPEFFTVLHSNPSAYRMFTNNTCLKHMITKVRRDTHHFER YQHNRDLVGFLNMFANKQLELPRGWEMKHDHQGKAFFVDHNSRTTTFIDPRLPLQSSRPTSALVHRQHLTRQRSHSAGEVGEDSRHAGPPVLPRPSSTFNTVSRPQYQDMVPVAYNDKIVAFLRQPNIFEILQERQPD Attorney Docket No.54926-0014WO1 LTRNHSLREKIQFIRTEGTPGLVRLSSDADLVMLLSLFEEEIMSYVPPHALLHPSYCQSPRGSPVSSPQ NSPGTQRANARAPAPYKRDFEAKLRNFYRKLETKGYGQGPGKLKLIIRRDHLLEDAFNQIMGYSRKDLQ RNKLYVTFVGEEGLDYSGPSREFFFLVSRELFNPYYGLFEYSANDTYTVQISPMSAFVDNHHEWFRFSG RILGLALIHQYLLDAFFTRPFYKALLRILCDLSDLEYLDEEFHQSLQWMKDNDIHDILDLTFTVNEEVF GQITERELKPGGANIPVTEKNKKEYIERMVKWRIERGVVQQTESLVRGFYEVVDARLVSVFDARELELV IAGTAEIDLSDWRNNTEYRGGYHDNHIVIRWFWAAVERFNNEQRLRLLQFVTGTSSIPYEGFASLRGSN GPRRFCVEKWGKITALPRAHTCFNRLDLPPYPSFSMLYEKLLTAVEETSTFGLE SEQ ID NO: 81 (WW1 (807-840)):EALPPNWEARIDSHGRIFYVDHVNRTTTWQRPTASEQ ID NO: 82 (WW2 (985-1018)): LELPRGWEMKHDHQGKAFFVDHNSRTTTFIDPRL SEQ ID NO: 83 (Human NLRP3, canonical) >sp|Q96P20|NLRP3_HUMAN NACHT, LRR and PYD domains-containing protein 3 OS=Homo sapiens OX=9606 GN=NLRP3 PE=1 SV=3 LEYLSRISICKMKKDYRKKYRKYVRSRFQCIEDRNARLGESVSLNKRYTRLRLIKEHRSQQEREQELLAIGKTKTCESPVSPIKMELLFDPDDEHSEPVHTVVFQGAAGIGKTILARKMM LDWASGTLYQDRFDYLFYIHCREVSLVTQRSLGDLIMSCCPDPNPPIHKIVRKPSRILFL MDGFDELQGAFDEHIGPLCTDWQKAERGDILLSSLIRKKLLPEASLLITTRPVALEKLQH LLDHPRHVEILGFSEAKRKEYFFKYFSDEAQARAAFSLIQENEVLFTMCFIPLVCWIVCTGLKQQMESGKSLAQTSKTTTAVYVFFLSSLLQPRGGSQEHGLCAHLWGLCSLAADGIWNQKILFEESDLRNHGLQKADVSAFLRMNLFQKEVDCEKFYSFIHMTFQEFFAAMYYLLEEEK EGRTNVPGSRLKLPSRDVTVLLENYGKFEKGYLIFVVRFLFGLVNQERTSYLEKKLSCKI SQQIRLELLKWIEVKAKAKKLQIQPSQLELFYCLYEMQEEDFVQRAMDYFPKIEINLSTR MDHMVSSFCIENCHRVESLSLGFLHNMPKEEEEEEKEGRHLDMVQCVLPSSSHAACSHGL VNSHLTSSFCRGLFSVLSTSQSLTELDLSDNSLGDPGMRVLCETLQHPGCNIRRLWLGRC GLSHECCFDISLVLSSNQKLVELDLSDNALGDFGIRLLCVGLKHLLCNLKKLWLVSCCLT SACCQDLASVLSTSHSLTRLYVGENALGDSGVAILCEKAKNPQCNLQKLGLVNSGLTSVC CSALSSVLSTNQNLTHLYLRGNTLGDKGIKLLCEGLLHPDCKLQVLELDNCNLTSHCCWD LSTLLTSSQSLRKLSLGNNDLGDLGVMMFCEVLKQQSCLLQNLGLSEMYFNYETKSALET LQEEKPELTVVFEPSW SEQ ID NO: 84 (Human GSDMD) c>sp|P57764|GSDMD_HUMAN Gasdermin-D OS=Homo sapiens OX=9606 GN=GSDMD Attorney Docket No.54926-0014WO1 IKDILEPDAAEPDVQRGRSFHFYDAMDGQIQGSVELAAPGQAKIAGGAAVSDSSSTSMNV YSLSVDPNTWQTLLHERHLRQPEHKVLQQLRSRGDNVYVVTEVLQTQKEVEVTRTHKREG SGRFSLPGATCLQGEGQGHLSQKKTVTIPSGSTLAFRVAQLVIDSDLDVLLFPDKKQRTF QPPATGHKRSTSEGAWPQLPSGLSMMRCLHNFLTDGVPAEGAFTEDFQGLRAEVETISKE LELLDRELCQLLLEGLEGVLRDQLALRALEEALEQGQSLGPVEPLDGPAGAVLECLVLSS GMLVPELAIPVVYLLGALTMLSETQHKLLAEALESQTLLGPLELVGSLLEQSAPWQERST MSLPPGLLGNSWGEGAPAWVLLDECGLELGEDTPHVCWEPQAQGRMCALYASLALLSGLS QEPH SEQ ID NO: 85 (Human IRF-5, canonical) >sp|Q13568|IRF5_HUMAN Interferon regulatory factor 5 OS=Homo sapiens OX=9606 GN=IRF5 PE=1 SV=2 CSNGPAPTDSQPPEDYSFGAGEEEEEEEELQRMLPSLSLTEDVKWPPTLQPPTLRPPTLQPPTLQPPVVLGPPAPDPSPLAPPPGNPAGFRELLSEVLEPGPLPASLPPAGEQLLPDLLI SPHMLPLTDLEIKFQYRGRPPRALTISNPHGCRLFYSQLEATQEQVELFGPISLEQVRFP SPEDIPSDKQRFYTNQLLDVLDRGLILQLQGQDLYAIRLCQCKVFWSGPCASAHDSCPNP IQREVKTKLFSLEHFLNELILFQKGQTNTPPPFEIFFCFGEEWPDRKPREKKLITVQVVP VAARLLLEMFSGELSWSADSIRLQISNPDLKDRMVEQFKELHHIWQSQQRLQPVAQAPPG AGLGVGQGPWPMHPAGMQ SEQ ID NO: 86 (Human IL-6) >sp|P05231|IL6_HUMAN Interleukin-6 OS=Homo sapiens OX=9606 GN=IL6 LDGISALRKETCNKSNMCESSKEALAENNLNLPKMAEKDGCFQSGFNEETCLVKIITGLL EFEVYLEYLQNRFESSEEQARAVQMSTKVLIQFLQKKAKNLDAITTPDPTTNASLLTKLQ AQNQWLQDMTTHLILRSFKEFLQSSLRALRQM SEQ ID NO: 87 (Human IL-12 subunit alpha) >sp|P29459|IL12A_HUMAN Interleukin-12 subunit alpha OS=Homo sapiens FYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMM ALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQK SSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS Attorney Docket No.54926-0014WO1 SEQ ID NO: 88 (Human IL-12 subunit beta) >sp|P29460|IL12B_HUMAN Interleukin-12 subunit beta OS=Homo sapiens OX=9606 GN=IL12B PE=1 SV=1 KEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERV RGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKN LQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVIC RKNASISVRAQDRYYSSSWSEWASVPCS SEQ ID NO: 89 (Human TNF) >sp|P01375|TNFA_HUMAN Tumor necrosis factor OS=Homo sapiens OX=9606 GN=TNF PE=1 SV=1 DNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQRE TPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIAL SEQ ID NO: 90 (Human GM-CSF) >sp|P04141|CSF2_HUMAN OS=Homo sapiens OX=9606 GN=CSF2 PE=1 SV=1 MWLQSLLLLG TVACSISAPA RSPSPSTQPW EHVNAIQEAR RLLNLSRDTA AEMNETVEVI SEMFDLQEPT CLQTRLELYK QGLRGSLTKL KGPLTMMASH YKQHCPPTPE TSCATQIITF ESFKENLKDF LLVIPFDCWE PVQE SEQ ID NO: 91 (Human PU.1) >sp|P17947|SPI1_HUMAN OS=Homo sapiens OX=9606 GN=SPI1 PE=1 SV=2 MLQACKMEGF PLVPPPSEDL VPYDTDLYQR QTHEYYPYLS SDGESHSDHY WDFHPHHVHS EFESFAENNF TELQSVQPPQ LQQLYRHMEL EQMHVLDTPM VPPHPSLGHQ VSYLPRMCLQ YPSLSPAQPS SDEEEGERQS PPLEVSDGEA DGLEPGPGLL PGETGSKKKI RLYQFLLDLLRSGDMKDSIW WVDKDKGTFQ FSSKHKEALA HRWGIQKGNR KKMTYQKMAR ALRNYGKTGEVKKVKKKLTY QFSGEVLGRG GLAERRHPPH OTHER EMBODIMENTS It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

Attorney Docket No.54926-0014WO1 WHAT IS CLAIMED IS:

1. An arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising: a lipid bilayer and an ARDDC1 protein, fragment thereof, or variant thereof; and a payload capable of modulating the sequence or expression of an inflammatory gene target.

2. A microvesicle producing cell comprising: nucleic acid construct(s) encoding: an ARRDC1 protein, fragment thereof, or variant thereof; and a payload capable of modulating the sequence or expression of an inflammatory gene target.

3. A method comprising administering an arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising a payload capable of modulating the sequence or expression of an inflammatory gene target to a cell, optionally the ARMM of claim 1.

4. A method for inhibiting cyotkine release in a cell, the method comprising administering an arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising a payload capable of modulating the sequence or expression of an inflammatory gene target to a cell, optionally the ARMM of claim 1.

5. A method for reducing inflammation in a cell, the method comprising administering an arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising a payload capable of modulating the sequence or expression of an inflammatory gene target to a cell, optionally the ARMM of claim 1.

6. A method for modulating the sequence or expression of an inflammatory gene target in the cell of a subject, the method comprising administering an arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising a payload capable of modulating the sequence or expression of an inflammatory gene target, optionally the ARMM of claim 1.Attorney Docket No.54926-0014WO1 7. The method of any one of claims 3–6, wherein the cell is a phagocyte.

8. The method of claim 7, wherein the cell is a macrophage.

9. The method of claim 8, wherein the macrophage is an alveolar macrophage.

10. The method of any one of claims 3–9, wherein the cell is the cell of a subject, and the method comprises administering the ARMM intranasally.

11. The method of claim 8, wherein the macrophage is a liver resident macrophage.

12. The method of claim 11, wherein the liver resident macrophage is a Kupffer cell.

13. The method of any one of claims 3–12, wherein the gene target is NLRP3, IRF-5, GSDMD, ASC, STING, IL-12, IL-10, TNF-alpha, IL-6, MCP-1, IL-33, TGF- beta, IL-27, GM-CSF, PU.1, PPARgamma, NOS, Lipoxin A4, CD86, CD80, and portions, and combinations thereof.

14. The method of claim 13, wherein the gene target is NLRP3.

15. A method for treating a disorder associated with mutation or dysregulation of an inflammatory gene target, the method comprising administering an arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising a payload capable of modulating the sequence or expression of an inflammatory gene target to a subject in need thereof, optionally the ARMM of claim 1.

16. The method of claim 15, wherein the disorder is selected from Allergic asthma, allergic rhinitis, chronic rhinosinusitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, atopic dermatitis, eosinophilic pneumonia, Crohn's disease, ulcerative colitis, psoriasis, rheumatoid arthritis (RA), primary Sjogren's syndrome, systemic sclerosis, gout, ankylosing spondylitis, pustular psoriasis, systemic lupus erythematosus (SLE), adult-onset Still's disease, Bechet’s disease,Attorney Docket No.54926-0014WO1 IgG4-related disease, cancer, MS, type1 diabetes, Sjogren's syndrome, atherosclerosis, acute respiratory distress syndrome (ARDS), acute lung injury, migraine, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, ischemic heart disease, diabetes, insulin-resistant diabetes, COVID-19, osteoarthritis, osteoporosis, ischemia-related neuronal death, excitotoxic neuronal injury, diabetes mellitus, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, lupus erythematosus, primary biliary cholangitis, Sjögren's syndrome, steroid-resistant asthma, allergic contact dermatitis, non-atopic eczema, dyslipidemia, diabetes, traumatic brain injury, ALS, Familiar cold-associated autoinflammatory syndrome, Muckle-Wells syndrome, urate crystal-induced peritonitis, acute myocardial infarction, psoriasis-like dermatitis, diabetic nephropathy, Stargardt disease type 1, atrial fibrillation, acute liver injury, nonalcoholic steatohepatitis (NASH), cirrhosis, cystic fibrosis, rheumatoid arthritis, celiac disease, asymmetrical septal hypertrophy (ASH), Silicosis, ischemia reperfusion, smoke / chemical injury, metal overload syndromes, Metabolic syndrome, type 2 diabetes, peripheral artery disease, renal disease, ulcerative colitis, myocardial ischemia / reperfusion injury, myocarditis, renal ischemia / reperfusion injury, renal fibrosis, diabetic kidney disease, periodontal disease, Minimal change disease, focal segmental glomerulosclerosis, graft-versus-host disease, polyarticular juvenile idiopathic arthritis, Hashimoto's thyroiditis, Grave's disease, Addison's disease, myasthenia gravis, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, polymyositis, scleroderma, Pulmonary alveolar proteinosis, interstitial lung disease, aortic aneurysm, obesity, axial spondyloarthritis, myelofibrosis, liver fibrosis, skin fibrosis, idiopathic pulmonary fibrosis, juvenile idiopathic arthritis, noninfectious uveitis, adult-onset Still's disease, giant cell arteritis, Takayasu arteritis, Castleman disease, cytokine release syndrome, uveitis, thyroid eye disease, erosive hand osteoarthritis, schizophrenia, Schnitzler syndrome, myocardial infarction, familiar Mediterranean fever, COVID-19 pneumonia, systemic scleroderma, myositis, pulmonary fibrosis, Aicardi-Goutières syndrome, COPA syndrome, and combinations thereof.

17. The ARMM of claim 1, the microvesicle producing cell of claim 2, or method of any one of claims 3–16, wherein the payload comprises a ribonucleoprotein.Attorney Docket No.54926-0014WO1 18. The ARMM, microvesicle producing cell, or method of claim 17, wherein the ribonucleoprotein comprises a nuclease, optionally a Cas9 nuclease, and a gRNA.

19. The ARMM, microvesicle producing cell, or method of claim 17 or claim 18, wherein the ribonucleoprotein is capable of knocking out or knocking down the expression of the inflammatory gene target.

20. The ARMM, microvesicle producing cell, or method of claim 17 or claim 18, wherein the inflammatory gene target is NLRP3, and the ribonucleoprotein is capable of introducing a loss of function mutation in promoter region and / or exon region.

21. The ARMM, microvesicle producing cell, or method of any one of claims 18– 20, wherein the inflammatory gene target is NLRP3, and wherein the gRNA comprises a sequence selected from any one of SEQ ID NOs: 1-34 and 92-114.

22. The ARMM, microvesicle producing cell, or method of any one of claims 18– 20, wherein the gRNA comprises a spacer region targeting the promoter region of NLRP3.

23. The ARMM, microvesicle producing cell, or method of claim 22, wherein the spacer region comprises or consists of the nucleic acid sequence of any one of SEQ ID NOs: 9 and 10.

24. The ARMM, microvesicle producing cell, or method of any one of claims 18– 20, wherein the gRNA comprises a spacer region targeting an exon of NLRP3.

25. The ARMM, microvesicle producing cell, or method of claim 24, wherein the spacer region comprises or consists of the nucleic acid sequence of any one of SEQ ID NOs: 97, 100, 101, 106, and 112.

26. The method of any one of claims 15–25, wherein the treatment target is NLRP3, the disorder is selected from familiar cold-associated autoinflammatory syndrome, Muckle-Wells syndrome, urate crystal-induced peritonitis, acute myocardial infarction, gout, psoriasis-like dermatitis, diabetic nephropathy, SLE, Stargardt disease type 1, Alzheimer's disease, atherosclerosis, atrial fibrillation,Attorney Docket No.54926-0014WO1 osteoarthritis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, cystic fibrosis, rheumatoid arthritis, ARDS, celiac disease, ASH, Silicosis, ischemia reperfusion, smoke / chemical injury, metal overload syndromes, and combinations thereof.

27. The method of claim 25, wherein the disorder is acute liver injury.

28. The method of any one of claims 15–19, wherein the treatment target is IRF-5, the disorder is selected from Sjogren's syndrome, rheumatoid arthritis, SLE, systemic scleroderma, multiple sclerosis, myositis, ulcerative colitis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, ARDS, and combinations thereof.

29. The method of any one of claims 15–19, wherein the treatment target is GSDMD, the disorder is selected from Familiar cold-associated autoinflammatory syndrome, Muckle-Wells syndrome, urate crystal-induced peritonitis, acute myocardial infarction, gout, psoriasis-like dermatitis, diabetic nephropathy, SLE, Stargardt disease type 1, Alzheimer's disease, atherosclerosis, atrial fibrillation, osteoarthritis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, cystic fibrosis, rheumatoid arthritis, ARDS, celiac disease, ASH, Silicosis, ischemia reperfusion, smoke / chemical injury, metal overload syndromes, and combinations thereof.

30. The methods of any one of the claims 15-19, wherein the treatment target is ASC, the disorder is selected from Familiar cold-associated autoinflammatory syndrome, Muckle-Wells syndrome, urate crystal-induced peritonitis, acute myocardial infarction, gout, psoriasis-like dermatitis, diabetic nephropathy, SLE, Stargardt disease type 1, Alzheimer's disease, atherosclerosis, atrial fibrillation, osteoarthritis, acute liver injury, NASH, cirrhosis, pulmonary fibrosis, cystic fibrosis, rheumatoid arthritis, ARDS, celiac disease, ASH, Silicosis, ischemia reperfusion, smoke / chemical injury, metal overload syndromes, and combinations thereof.

31. The method of any one of claims 15–19, wherein the treatment target is STING, the disorder is selected from SLE, Aicardi-Goutières syndrome, COPA syndrome, Alzheimer disease, Parkinson disease, ALS, and combinations thereof.Attorney Docket No.54926-0014WO1 32. The method of any one of claims 15–19, wherein the treatment target is IL-12, the disorder is selected from Crohn's disease, ulcerative colitis, psoriasis, diabetes mellitus, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, lupus erythematosus, primary biliary cholangitis, Sjögren's syndrome, and combinations thereof.

33. The method of any one of claims 15–19, wherein the treatment target is IL-10, the disorder is selected from Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, allergic asthma, steroid-resistant asthma, allergic contact dermatitis, non- atopic eczema, dyslipidemia, diabetes, atherosclerosis, MS, traumatic brain injury, ALS, Alzheimer's disease, Parkinson's disease, and combinations thereof.

34. The method of any one of claims 15–19, wherein the treatment target is TNF- alpha, the disorder is selected from Rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis, psoriasis, noninfectious uveitis, ankylosing spondylitis, and combinations thereof.

35. The method of any one of claims 15–19, wherein the treatment target is IL-6, the disorder is selected from Rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, giant cell arteritis, Takayasu arteritis, Castleman disease, SLE, systemic sclerosis, cytokine release syndrome, uveitis, thyroid eye disease, erosive hand osteoarthritis, schizophrenia, Schnitzler syndrome, myocardial infarction, familiar Mediterranean fever, COVID-19 pneumonia, and combinations thereof.

36. The method of any one of claims 15–19, wherein the treatment target is MCP- 1, the disorder is selected from Alzheimer's disease, Parkinson's disease, epilepsy, MS, atherosclerosis, stroke, ischemic heart disease diabetes, insulin-resistant diabetes, COVID-19, osteoarthritis, RA, osteoporosis, allergic asthma, ischemia-related neuronal death, exitotoxic neuronal injury, and combinations thereof.

37. The method of any one of claims 15–19, wherein the treatment target is IL-33, the disorder is selected from Allergic asthma, allergic rhinitis, chronic rhinosinusitis, COPD, pulmonary fibrosis, atopic dermatitis, eosinophilic pneumonia, Crohn'sAttorney Docket No.54926-0014WO1 disease, ulcerative colitis, psoriasis, psoriatic arthritis, RA, primary Sjogren's syndrome, systemic sclerosis, gout, ankylosing spondylitis, pustular psoriasis, SLE, adult-onset Still's disease, Behcet's disease, IgG4-related disease, and combinations thereof.

38. The method of any one of claims 15–19, wherein the treatment target is TGF- beta, the disorder is selected from Pulmonary fibrosis, myelofibrosis, liver fibrosis, NASH, skin fibrosis, renal fibrosis, idiopathic pulmonary fibrosis, cancer, and combinations thereof.

39. The method of any one of claims 15–19, wherein the treatment target is IL-27, the disorder is selected from Allergic asthma, allergic rhinitis, cancer, MS, type 1 diabetes, Sjogren's syndrome, Crohn's disease, ulcerative colitis, atherosclerosis, and combinations thereof.

40. The method of any one of claims 15–19, wherein the treatment target is GM- CSF, the disorder is selected from Pulmonary alveolar proteinosis, RA, osteoarthritis, MS, Crohn's disease, ulcerative colitis, interstitial lung disease, aortic aneurysm, allergic asthma, obesity, COVID-19, psoriasis, axial spondylarthritis, ankylosing spondylitis, and combinations thereof.

41. The method of any one of claims 15–19, wherein the treatment target is PU.1, the disorder is selected from Pulmonary alveolar proteinosis, Grave's disease, Hashimoto's thyroiditis, MS, RA, psoriatic arthritis, psoriasis, systemic sclerosis, SLE, Sjogren's syndrome, primary biliary cirrhosis, type 2 diabetes, Alzheimer's disease, Parkinson's disease, allergic asthma, and combinations thereof.

42. The method of any one of claims 15–19, wherein the treatment target is PPARgamma, the disorder is selected from Pulmonary alveolar proteinosis, Grave's disease, Hashimoto's thyroiditis, MS, RA, psoriatic arthritis, psoriasis, systemic sclerosis, SLE, Sjogren's syndrome, primary biliary cirrhosis, type 2 diabetes, Alzheimer's disease, Parkinson's disease, allergic asthma, and combinations thereof.Attorney Docket No.54926-0014WO1 43. The method of any one of claims 15–19, wherein the treatment target is NOS, the disorder is selected from Allergic asthma, ARDS, acute lung injury, RA, Alzheimer's, Parkinson's, pulmonary fibrosis, atherosclerosis, migraine, and combinations thereof.

44. The method of any one of claims 15–19, wherein the treatment target is Lipoxin A4, the disorder is selected from Metabolic syndrome, type 2 diabetes, peripheral artery disease, renal disease, COPD, Crohn's disease, ulerative colitis, RA, cancer, Alzheimer's disease, stroke, atherosclerosis, myocardial ischemia / reperfusion injury, myocarditis, acute lung injury, allergic asthma, pulmonary fibrosis, cystic fibrosis, renal ischemia / reperfusion injury, renal fibrosis, diabetic kidney disease, periodontal disease, and combinations thereof.

45. The method of any one of claims 15–19, wherein the treatment target is CD86, the disorder is selected from Minimal change disease, focal segmental glomerulosclerosis, psoriasis, psoriatic arthritis, RA, graft-versus-host disease, polyarticular juvenile idiopathic arthritis, type 1 diabetes, MS, SLE, Hashimoto's thyroiditis, Grave's disease, Addison's disease, Crohn's disease, ulcerative colitis, myastenia gravis, sympathetic ophtalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, Sjogren's syndrome, polymyositis, scleroderma, and combinations thereof.

46. The method of any one of claims 15–19, wherein the treatment target is CD80, the disorder is selected from Minimal change disease, focal segmental glomerulosclerosis, psoriasis, psoriatic arthritis, RA, graft-versus-host disease, polyarticular juvenile idiopathic arthritis, type 1 diabetes, MS, SLE, Hashimoto's thyroiditis, Grave's disease, Addison's disease, Crohn's disease, ulcerative colitis, myastenia gravis, sympathetic ophtalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, Sjogren's syndrome, polymyositis, scleroderma, and combinations thereof.

47. The method of any one of claims 15-19 wherein the subject is experiencing inflammation of one or more tissues.Attorney Docket No.54926-0014WO1 48. The method of any one of claims 15-25, wherein the subject is experiencing inflammation of liver tissue.

49. The method of claim 48, wherein the subject has acute liver injury.

50. The method of claim 47, wherein the subject is experiencing inflammation of lung tissue.

51. The method of claim 50, wherein the subject has acute lung injury.

52. The method of claim 50, wherein the subject has interstitial lung disease.

53. The method of any one of claims 15-52, wherein the administration is intravenous administration.

54. The method of any one of claims 15-52, wherein the administration is by inhalation.

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